Plasminogen Activity Research Articles

Blood biomarkers and measures of pulmonary function–A study from the Swedish twin registry

There is great need of biomarkers for research and clinical purposes in COPD. This study explored the relationships between ten putative plasma biomarkers of COPD and physiological measures of reduced lung function. FEV(1), FVC, residual volume/total lung capacity (RV/TLC) and CO diffusion capacity (D(L)CO) were assessed in 357 subjects from the Swedish Twin Registry. The lung function measures were studied in relation to plasma levels of desmosines, C-reactive protein (CRP), plasminogen inhibitor activator (PAI-1) concentration and activity, tissue inhibitor of metalloproteinase (TIMP-1), clara cell protein 16 (CC16), surfactant protein D (SPD), matrix metalloproteinase 9 (MMP-9), hepatocyte growth factor (HGF) and interleukin (IL)-8. After adjustments for age, sex, height, BMI and smoking, FEV(1) was significantly associated with PAI-1 activity and desmosines. RV/TLC was significantly associated with CC16, PAI-1 concentration and PAI-1 activity, and D(L)CO was significantly associated with desmosines, TIMP-1 and CRP. When the multivariate analysis was restricted to subjects with COPD (i.e., FEV(1)/FVC < 0.70), CRP and desmosines were inversely associated with lung function. Several biomarkers were associated with lung function in this cross-sectional study. Especially CRP and desmosines could be useful markers to assess disease severity in subjects with COPD.

Interrelationships between somatic cell counts, lactation stage and lactation number and their influence on plasmin activity and protein fraction distribution in dromedary (Camelus dromedaries) and cow milks

In the present study, the relationship between milk somatic cell counts (SCC), nitrogen fractions, individual casein percentage distribution, plasmin-plasminogen activities and proteolysis, and the influence of lactation stage and lactation number in dromedary and cow milks were compared. Dromedary milk appeared to contain a lower amount of total and pH 4.6-soluble nitrogen than cow milk. The major protein components in milks were caseins, which accounted for ∼70% of total proteins for both species, β- and αs1-being the predominant caseins in both milk kinds. In dromedary milk, β-casein increased with lactation number but decreased as SCC increased. Total protein, αs2-casein and SCC decreased during lactation in dromedary milk. The dromedary is characterized by a relatively low content of κ-casein.Plasmin plus plasminogen activity is higher in cow milk compared to dromedary milk. The plasmin activity increased as SCC increased in cow milk but not in dromedary milk.

Fibrinolytic status in acute coronary syndromes: Evidence of differences in relation to clinical features and pathophysiological pathways

Limited data are available on the role of innate fibrinolysis in acute coronary syndromes (ACS). In the present study we evaluated the dynamic alterations of fibrinolytic markers in patients presenting with ACS. Tissue-type-(tPA) and urokinase type-(uPA) plasminogen activators, plasminogen activator inhibitor (PAI-1) antigen and activity and thrombin activatable fibrinolysis inhibitor (TAFI) were analysed in 50 patients with ST elevation myocardial infarction (STEMI), 47 non-STEMI patients (NSTEMI), 40 patients with stable coronary artery disease (CAD) and 39 controls. The parameters were measured on day 1 and days 3, 7 and 30. Counts of monocyte subsets, monocyte-platelet aggregates and plasma inflammatory cytokines were assessed on admission. On day 1, TAFI was higher in NSTEMI vs. STEMI (p<0.001) while PAI-1 activity was higher in STEMI (p<0.001). In STEMI, uPA activity levels was low on day 1 but significantly increased on day 30 (p<0.001). TAFI levels were increased in NSTEMI on day 1 and gradually reduced by day 30 (p<0.05). In STEMI, TAFI levels peaked at day 7 (p<0.05) and dropped significantly by day 30 (p<0.05). CD14++CD16+ monocytes were independently associated with PAI-1 activity in ACS (p=0.03). Monocyte-platelet aggregates rather than platelet-free monocytes were an independent determinant of tPA, PAI-1 antigen and TAFI on a multivariate analysis (p<0.05). There are significant differences in fibrinolytic activity between patients with STEMI and NSTEMI. These changes could reflect the role of these factors in post-MI myocardial healing. Monocyte-platelet interactions are independently associated with the regulation of the fibrinolytic status in ACS.

A history of early stent thrombosis is associated with prolonged clot lysis time

It has been demonstrated that formation of compact plasma fibrin clots resistant to plasmin-mediated lysis characterises patients following in-stent thrombosis (IST). The relationship between defective fibrinolysis, reflected as prolonged clot lysis time (CLT) and IST is unclear. We sought to investigate whether patients with acute and subacute IST have impaired fibrinolytic capacity. We studied 41 definite IST patients, including 15 with acute and 26 with subacute IST experienced 2-73 months prior to enrollment, versus 41 controls matched for demographics, cardiovascular risk factors, concomitant treatment and angiographic/stent parameters. CLT, reflecting lysis of a tissue factor-induced plasma clot by exogenous tissue plasminogen activator, together with plasminogen activator inhibitor-1 (PAI-1) antigen and activity, thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and activity, thrombomodulin (TM), plasminogen and α2-antiplasmin (α2AP) were measured. There were no inter-group differences in angiographic parameters, indication to the first PCI, culprit vessel or a type of stent. Patients with IST had 11% longer CLT (p=0.005) and 13% higher PAI-1 antigen (p=0.04) compared to controls. There were positive correlations in both groups between CLT and PAI-1 antigen and TAFI activity (all p<0.001). Multiple regression analysis showed that CLT (odds ratio [OR]=1.04 per 1 minute, 95% CI 1.01-1.08, p=0.02) and platelet count (OR=1.01 per 1,000/μl, 95% CI 1.00-1.02, p=0.034) were independent predictors of IST (R(2)=0.28, p<0.05). Concluding, impaired fibrinolytic potential, that is in part determined by plasma PAI-1 antigen and TAFI activity, characterises patients with a history of acute and subacute IST, which might help identify patients at higher risk of IST.

Comparison of plasma and peritoneal indices of fibrinolysis between foals and adult horses with and without colic

To identify hemostatic imbalances indicative of an increased risk of intra-abdominal adhesion formation in foals versus adult horses. Horses with colic undergoing exploratory laparotomy or abdominocentesis as part of a clinical examination (n = 16 foals ≤ 6 months of age and 19 adults ≥ 5 years of age) and horses without colic undergoing herniorrhaphy (15 foals) or euthanasia for noninflammatory and nongastrointestinal disease (10 foals and 20 adults). Paired abdominal fluid and blood samples were collected from each horse into buffered sodium citrate and centrifuged immediately after collection. Supernatants were stored at -80°C, then thawed for measurement of fibrinogen concentration, plasminogen activity, antiplasmin activity, and D-dimer concentration. Supernatant analyte concentrations or activities were compared within age group (foals with and without colic vs adults with and without colic) and within disease status (foals and adults without colic vs foals and adults with colic). All analyte concentrations or activities in abdominal fluid samples were significantly lower in the noncolic groups than in the colic groups, and none differed between foal and adult groups. Several plasma analyte values differed by disease status and age. The risk of intra-abdominal adhesion formation in the foals in this study did not appear to be attributable to differences in intra-abdominal hemostasis between adult horses and foals. Strategies for initial medical and surgical management of colic in adult horses may be applicable to foals with similar disorders.

Add-on rosiglitazone therapy improves plasminogen activity and high-density lipoprotein cholesterol in type 2 diabetes mellitus

Rosiglitazone is an oral hypoglycaemic agent of the thiazolidinedione group. This study aimed to assess changes in the diabetic prothrombotic state via plasminogen activity and changes in surrogate markers of atherosclerotic burden via ankle-brachial pressure index (ABPI) measurements after rosiglitazone was added to a pre-existing type 2 diabetes mellitus treatment regime. A nonblinded interventional study was designed. Fifty-nine patients were enrolled. Rosiglitazone-naïve patients were prescribed oral rosiglitazone 4 mg daily for 10 weeks. ABPI, plasminogen activity, glycosylated haemoglobin (HbA1c) and fasting lipid profile were measured pretreatment and post-treatment. Forty-eight patients completed the study. At the end of this study, mean plasminogen activity improvement was nearly 16% (P<0.05), mean ABPI improvement was 0.01 (P=0.439), mean HbA1c reduction was 0.51% (P<0.05), mean total cholesterol (TC) increase was 0.36 mmol/l (P<0.05), mean high-density lipoprotein cholesterol (HDL-C) increase was 0.15 mmol/l (P<0.05) and mean low-density lipoprotein cholesterol increased by 0.19 mmol/l (P=0.098). Rosiglitazone significantly improved plasminogen activity. There was also significant HbA1c reduction, and rise in both TC and HDL-C. Thus, rosiglitazone potentially improves the atherosclerotic burden and prothrombotic state. In future, more studies are needed to confirm the relationship between rosiglitazone, fibrinolytic system and atheromatous reduction in type 2 diabetes mellitus.

A pilot study on purification of human plasminogen from cord blood plasma and inducing posterior vitreous detachment

Background Many studies and clinical trials of pharmacologic vitreolysis are already under way to try to improve vitreo-retinal surgery and to liquefy and detach the vitreous from the retina ultimately, including chondroitinase,hyaluronidase,dispase and plasmin. However, there has not been any report on purification of human plasminogen from cord blood plasma and inducing posterior vitreous detachment of the animal eye at present.Objective This study was designed to isolate and purify the production of human plasminogen (Plg) from cord blood plasma with ethanol precipitation and evaluate the efficacy of Plg in inducing posterior vitreous detachment (PVD).Methods Human Plg was Separated and purified from cord blood plasma by ethanol precipitation method. The protein band corresponding to Plg with molecular mass of 92 000 was revealed in SDS-PAGE and confirmed by MALDI-TOF and Mascot database. Anion-exchange chromatography and plasminogen activity assay kit were used to obtain purified Plg with biological activity. Twenty-five fresh pig eyes were enucleated and assigned to 5 groups and 5 eyes for each group. The normal eyes were used as control group. Balanced salt solution(BSS)of 0.1 ml was intravitreally group and standard substance group. All of the eyes were then incubatedfor 60 minutes under the 37 ℃. Retinal histopathology and ultrastructure were examined under the light microscopy, scanning electron microscopy ( SEM ) and transmission electron microscopy (TEM). Results The Plg with potential fibrinolytic activity was successfully extracted and purified from cord blood plasma by ethanol precipitation method. No posterior vitreous detachment (PVD) was seen in normal control group, BSS group and r-SK group following the intravitreal injection under the sem. However,PVD was demonstrated in r-SK+ Plg group and standard substance group under the SEM. The inner limiting membrane ( ILM ) and the retina were well preserved in all of the experimental eyes. No retinal morphology and ultrastructural abnormality were found under the light and SEM and TEM. Conclusion Ethanol precipitation is a feasible way to isolate and purify Plg from human cord blood plasma. Extracted Plg shows potential fibrinolytic intravitreal injection of Plg. Key words: Human plasminogen; Recombinant streptokinase; Cord blood; Posterior vitreous detachment

Management of ligneous conjunctivitis in a child with plasminogen deficiency

Plasminogen deficiency, a rare autosomal recessive disorder, is classified as type I (hypoplasminogenemia) or type II (dysplasminogenemia). Hypoplasminogenemia is characterized by impaired wound healing while ligneous conjunctivitis (LC) is its main manifestation presenting with redness of the conjunctivae and progression to pseudomembranes' formation on the palpebral surfaces. A 4-year-old girl with LC in her left eye and impaired vision was referred to our unit. The conjunctival membranes had been already excised twice, followed by recurrences. Soon after the third recurrence, a probable diagnosis of LC was suggested, confirmed by a reduced plasminogen activity at 20% (normal values 80-120%). Both of her parents have slightly reduced plasminogen levels (50-60%) without any relevant symptom. Fresh frozen plasma (FFP) was administered systemically and topically, initiating 2 days before surgical removal of pseudomembranes with electrocautery under general anaesthesia. Systemic FFP was administered for 12 days postoperatively, along with topical use; the later was continued thereafter for 3 months. No recurrence was noticed. The vision was improved. Two weeks after cessation of the topical treatment, pseudomembranes reappeared. Topical application of FFP was reinitiated soon thereafter, and the girl underwent a second operation to have the conjunctival pseudomembranes removed. The perioperative therapeutic management was as previously described. Systemic treatment was stopped at the end of the tenth day while topical application of FFP was being continued until now, 10 months postoperatively. No recurrence has been observed and the vision remains at 9/10. Since surgical excision of the conjunctival pseudomembranes alone in patients with LC does not protect from recurrences, the perioperative administration of FFP, both systemically and topically improves the outcome. Furthermore, the long-term application of topical FFP preparations seems to prevent recurrences and has a protective effect on the vision of these patients.

Prepubertal Vaginitis as the Presenting Sign of Systemic Hematologic Dysfuntion

Plasminogen deficiency is a rare congenital anomaly in which decreased plasminogen activity results in an inability to breakdown fibrin and subsequent pseudomembrane formation. Only 8% of symptomatic patients develop ligneous changes of the genital tract. Fibrin deposition is precipitated by irritation, infection and inflammation. Involvement of the female reproductive tract is hypothesized to be related to sexual activity and typically presents in adult life. We describe the rare case of a prepubertal girl whose presenting sign of plasminogen deficiency was vulvovaginitis.

The effect of the fibrinolytic enzyme FIIa from Agkistrodon acutus venom on acute pulmonary thromboembolism.

To evaluate the effects of the fibrinolytic enzyme FII(a) from Agkistrodon acutus venom on acute pulmonary thromboembolism (APT) in animal models. Both rabbit and dog APT models were used. For the rabbit APT model, the thrombi weight before and after administration was measured. Central venous pressure (CVP) and mean arterial pressure (MAP) were measured before and 15, 30, 60, and 120 min after the injection of the blood clot. Partial thromboplastin time (APTT), prothrombin time (PT), platelet count, and fibrinogen concentration were measured using auto analyzers. Plasminogen activity was measured based on chromogenic substrates. In the dog APT model, pulmonary blood flow was recorded using pulmonary angiography. Intravenous administration of FIIa (0.1-5.0 mg/kg) improved the APT-induced hemodynamic derangements and reduced thrombi weight. The angiography evidence also showed that the pulmonary emboli had almost disappeared after FII(a) infusion. FII(a) (0.1, 0.5, or 1.0 mg/kg) did not impair the coagulation pathways, although very high doses of FII(a) (5.0 mg/kg) could stimulate the production of plasminogen and result in impairment of the pathways. FII(a) could effectively protect against APT via degradation of thrombi with less activation of plasminogen, and may provide a novel fibrinolytic enzyme for targeting the main pathological processes of the disease.

Suppression of Osteosarcoma Cell Invasion by Chemotherapy Is Mediated by Urokinase Plasminogen Activator Activity via Up-Regulation of EGR1

BackgroundThe cellular and molecular mechanisms of tumour response following chemotherapy are largely unknown. We found that low dose anti-tumour agents up-regulate early growth response 1 (EGR1) expression. EGR1 is a member of the immediate-early gene group of transcription factors which modulate transcription of multiple genes involved in cell proliferation, differentiation, and development. It has been reported that EGR1 act as either tumour promoting factor or suppressor. We therefore examined the expression and function of EGR1 in osteosarcoma.MethodsWe investigated the expression of EGR1 in human osteosarcoma cell lines and biopsy specimens. We next examined the expression of EGR1 following anti-tumour agents treatment. To examine the function of EGR1 in osteosarcoma, we assessed the tumour growth and invasion in vitro and in vivo.ResultsReal-time PCR revealed that EGR1 was down-regulated both in osteosarcoma cell lines and osteosarcoma patients' biopsy specimens. In addition, EGR1 was up-regulated both in osteosarcoma patient' specimens and osteosarcoma cell lines following anti-tumour agent treatment. Although forced expression of EGR1 did not prevent osteosarcoma growth, forced expression of EGR1 prevented osteosarcoma cell invasion in vitro. In addition, forced expression of EGR1 promoted down-regulation of urokinase plasminogen activator, urokinase receptor, and urokinase plasminogen activity. Xenograft mice models showed that forced expression of EGR1 prevents osteosarcoma cell migration into blood vessels.ConclusionsThese findings suggest that although chemotherapy could not prevent osteosarcoma growth in chemotherapy-resistant patients, it did prevent osteosarcoma cell invasion by down-regulation of urokinase plasminogen activity via up-regulation of EGR1 during chemotherapy periods.

Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity

Inherited severe hypoplasminogenaemia is a multisystemic disorder leading to deficient extravascular fibrinolysis. As a clinical consequence wound healing capacity of mucous membranes is markedly impaired leading to ligneous conjunctivitis and several other manifestations. Here we report the molecular genetic and clinical findings on 23 new cases with severe hypoplasminogenaemia. Homozygous or compound-heterozygous mutations in the plasminogen (PLG) gene were found in 16 of 23 patients (70%), three of which were novel mutations reported here for the first time (C166Y, Y264S, IVS10-7T/G). Compared to 79 previously published cases, clinical manifestations of the current group of patients showed higher percentages of ligneous periodontitis, congenital hydrocephalus, and involvement of the female genital tract. In contrast, involvement of the gastrointestinal or urogenital tract was not observed in any of the cases. Patients originated to a large extent (61%) from Turkey and the Middle East, and showed a comparably frequent occurrence of consanguinity of affected families and a greater female to male ratio than was derived from previous reports in the literature. Individual treatment of ligneous conjunctivitis included topical plasminogen or heparin eye drops, topical or systemic fresh frozen plasma, and surgical removal of ligneous pseudomembranes, mostly with modest or transient efficacy. In conclusion, the present study underscores the broad range of clinical manifestations in PLG-deficient patients with a trend to regional differences. Transmission of genetic and clinical data to the recently established Plasminogen Deficiency Registry should help to determine the prevalence of the disease and to develop more efficient treatment strategies.

Atividade de plasmina e plasminogênio no leite longa vida com alta e baixa contagem de células somáticas durante o armazenamento

O objetivo deste estudo foi avaliar o efeito da contagem de células somáticas (CCS) do leite na atividade de plasmina e plasminogênio durante o período de armazenamento do leite longa vida integral. Os leites crus foram categorizados em grupos de CCS de baixa (342.000-487.000 células mL-1) e alta contagem (603.000-808.000 células mL-1). Dois lotes de leite longa vida em cada categoria de CCS foram analisados para determinação de plasmina e plasminogênio após 10, 30, 60, 90 e 120 dias de armazenamento em temperatura ambiente. Para a fabricação do leite longa vida, o leite cru foi submetido à pasteurização rápida seguida da esterilização industrial do leite por injeção de vapor pelo método direto e embalagem asséptica do produto. A CCS não apresentou efeitos sobre as características físico-químicas do leite cru, e nem sobre a atividade de plasmina e plasminogênio nos leites cru e longa vida, armazenados por 120 dias. Entretanto, independentemente da CCS, a atividade de plasmina e plasminogênio aumentou no leite longa vida ao longo do armazenamento, indicando a possibilidade de aumento da proteólise no produto durante sua vida de prateleira.

Anti-invasion effects of 6-shogaol and 6-gingerol, two active components in ginger, on human hepatocarcinoma cells.

Hepatocellular carcinoma is the most common type of liver cancer and is highly metastatic. Metastasis is considered to be the major cause of death in cancer patients. Ginger is a natural dietary rhizome with anti-oxidative, anti-inflammatory, and anti-carcinogenic activities. The aims of this study were to evaluate the anti-invasion activity of 6-shogaol and 6-gingerol, two compounds found in ginger, on hepatoma cells. The migratory and invasive abilities of phorbol 12-myristate 13-acetate (PMA)-treated HepG2 and PMA-untreated Hep3B cells were both reduced in a dose-dependent manner by treatment with 6-shogaol and 6-gingerol. Upon incubation of PMA-treated HepG2 cells and PMA-untreated Hep3B cells with 6-shogaol and 6-gingerol, matrix metalloproteinase (MMP)-9 activity decreased, whereas the expression of tissue inhibitor metalloproteinase protein (TIMP)-1 increased in both cell types. Additionally, urokinase-type plasminogen activator activity was dose-dependently decreased in Hep3B cells after incubation with 6-shogaol for 24 h. Analysis with semi-quantitative reverse transcription-PCR showed that the regulation of MMP-9 by 6-shogaol and 6-gingerol and the regulation of TIMP-1 by 6-shogaol in Hep3B cells may on the transcriptional level. These results suggest that 6-shogaol and 6-gingerol might both exert anti-invasive activity against hepatoma cells through regulation of MMP-9 and TIMP-1 and that 6-shogaol could further regulate urokinase-type plasminogen activity.

Imbalance of Plasminogen Activator Inhibitor Type-1 (PAI-1) and Tissue Plasminogen Activator (t-PA) Activity in Patients With Noonan Syndrome

Patients with Noonan syndrome have been reported to have an increased incidence of bleeding with trauma and surgery. Although various abnormalities of hemostasis have been described in reported series, there has been no consistent abnormality described and none have investigated fibrinolytic pathways. Fibrinolytic parameters including tissue plasminogen activator (t-PA; activity and antigen), plasminogen activator inhibitor type-1 (PAI-1; activity and antigen), plasminogen (activity and antigen), thrombin-antithrombin complex, prothrombin time (PT), and activated partial thromboplastin time where studied in 12 patients with Noonan syndrome (total of 15 data sets). PT and activated partial thromboplastin time were performed locally whereas the fibrinolytic parameters were performed in a single national reference laboratory. Individual results were compared with published age-appropriate norms and the mean values of the study patients were compared with the midpoint of normal range for each component measured. The ratio of PAI-1/t-PA activity was calculated for each set of results and compared with a "normal" value calculated from the midpoint normal range value for each component. Patients with Noonan syndrome consistently demonstrated an elevation of t-PA activity in relationship to PAI-1 activity and a decreased PAI-1/t-PA ratio (P<0.01 for each comparison). Patients with Noonan syndrome seem to have an imbalance in fibrinolytic components favoring fibrinolysis. This may be an important contributor to the bleeding noted in these patients.

Invasive infection caused by Streptococcus dysgalactiae subsp. equisimilis: characteristics of strains and clinical features

Among clinically isolated β-hemolytic streptococci, Streptococcus pyogenes and S. agalactiae were considered the main pathogens in humans until recently. In 1996, S. dysgalactiae subsp. equisimilis (SDSE) was proposed as a novel taxon among human-derived streptococcal isolates. SDSE has Lancefield group C or G antigens, exhibits strong β-hemolysis, and exerts streptokinase activity upon human plasminogen and proteolytic activity upon human fibrin. Similarly to group A streptococci, SDSE possesses virulence factors including M protein, streptolysin O, streptolysin S, streptokinase, hyaluronidase, C5a peptidase, and others. SDSE may exist among the normal flora of the skin, oropharynx, and gastrointestinal and genitourinary tracts. In the twenty-first century, invasive SDSE infection (i.e., cellulitis, urosepsis, and pneumonia) leading to various disseminated diseases is being diagnosed increasingly in Japan, elsewhere in Asia, in Europe, and in America. Particularly, among elderly patients, these invasive diseases are encountered increasingly in Japanese hospital emergency departments. Analysis of the part of the emm gene encoding the amino acid sequence at the N-terminal end of the M protein is used to determine the molecular epidemiology of SDSE. The distribution of emm types from patients with invasive or noninvasive infections differs between surveillance results from different countries. In this review, we summarize the characteristics of phenotypes and virulence factors in SDSE strains; the review also focuses on emerging SDSE infectious disease and future vaccination research.

Effects of Simulated Bleeding in an in Vitro Nasal Fibroblast Wound Healing Model

We investigated the effect of simulated bleeding on plasminogen activity, matrix metalloproteinase (MMP) expression, and wound healing using a human fibroblast model. Nasal fibroblasts from three chronic rhinosinusitis (CRS) patients with nasal polyps and three controls were grown in culture and a standardized injury was created using a punch. To mimic bleeding, fibroblasts were stimulated with plasminogen (100 microg/mL), plasminogen + tranexamic acid (TA; 100 microg/mL) or media only. At 24, 48, and 72 hours after injury, we measured urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activities and inactive and active MMP-2 and -9 expression. Injury stimulated the nasal fibroblasts to express uPA and tPA and active and inactive MMP-2 and -9. In CRS patients, plasminogen significantly decreased MMP-9 expression after 48 hours (p < 0.04). In untreated fibroblasts, we observed a decrease in active MMP-9 expression, whereas plasminogen increased active MMP-9 expression after 48 hours (p < 0.04). At 24 hours, active MMP-9 expression was reduced by plasminogen +/- TA (p < 0.02). Plasminogen also stimulated uPA expression in CRS patient fibroblasts after 48 hours (p < 0.04). Fibroblast proliferation occurred when exposed to plasminogen and was strongly modulated by uPA and inactive and active MMP-2. The quality of wound healing was affected by inactive MMP-2, uPA and tPA, simulation, and inhibition of bleeding. Activation of the plasminogen pathway and inactive MMP-2 expression tended to increase both proliferation of nasal fibroblasts and MMP-9 expression as a marker for deterioration of the quality of wound healing.

Fibrinolytic parameters, lipid status and lipoprotein(a) in ischemic stroke patients

Ischemic stroke is the third leading cause of mortality and morbidity in most countries in the world. Impaired fibrinolysis, as well as disordered lipid metabolism have been recognized as risk factors for this disease. To study some of fibrinolytic parameters, lipid status and lipoprotein(a) - Lp(a) in ischemic stroke patients in Serbia and to examine associations between Lp(a) and fibrinolytic parameters. Sixty ischemic stroke patients (case group, mean age 63.48 +/- 9.62 years) and 30 age and sex matched healthy controls (control group, mean age 60.2 +/- 7.96 years) were studied. A significantly longer euglobulin clot lysis time (219.7 +/- 78,8 min. vs 183.5 +/- 58,22 min; p = 0.005) and higher levels of plasminogen activator inhibitor-1 (PAI-1) (48.5 +/- 17.1 ng/ml vs 27.1 +/- 10.1 ng/ml; p = 6.2 x 10(-11)), tissue-type plasminogen activator antigen (t-PA) (11.1 +/- 7.14 ng/ml vs 6.0 +/- 3.66 ng/ml; p = 5.2 x 10(-5)) and D-dimer (382.27 +/- 504.22 ng/ml vs 116.12 +/- 88.81 ng/ml; p = 0.0002) were found in cases compared to controls. There were no significant differences in fibrinogen levels (4.30 +/- 0.84 g/l vs 4.09 +/- 0.64 g/l; p = 0.23) or plasminogen activity (92.67 +/- 11.37% vs 96.87 +/- 9.48%; p = 0.085). There was no significant difference in Lp(a) concentration between cases and controls (0.15 +/- 0.11 g/l vs 0.12 +/- 0.11 g/l; p = 0.261). However, in the cases, but not in the controls, multivariate analysis of associations between fibrinolytic parameters and Lp(a) showed the highest correlation between t-PA and PAI-1, and the latent effect of Lp(a) on t-PA and PAI-1. Our results show that there are important differences in the characteristics of the fibrinolytic mechanism in ischemic stroke patients compared to healthy population. The major differences are prolonged euglobulin clot lysis time and elevated PAI-1 and t-PA antigen in ischemic stroke patients. In addition, Lp(a) appears to be involved in the inhibition offibrinolysis in ischemic disease through a mechanism unrelated to its serum concentrations.

Effects of Glimepiride on metabolic parameters and cardiovascular risk factors in patients with newly diagnosed type 2 diabetes mellitus

Background To investigate the effects of Glimepiride on blood glucose in patients with newly diagnosed type 2 diabetes mellitus (T2DM) in connection with plasma lipoproteins and plasminogen activity. Methods A total of 565 T2DM patients were received Glimepiride ( n = 333) or Glibenclamide ( n = 232) for 12 weeks. We observed the level of blood glucose (BG), glycated hemoglobin (HbA1C), the insulin resistance (IR) state, plasma lipoproteins, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type I (PAI-1) before and after a 12 weeks of treatment. Results After 12 weeks with Glimepiride treatment, significant reductions were observed in fasting blood glucose (FBG) and 2-h postprandial BG(PBG), HbA1C (from 8.60 ± 3.10 to 7.10 ± 1.60%) and HOMA-IR (from 4.11 ± 0.85 to 2.42 ± 0.91%). The level of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were significantly decreased, whereas that of high-density lipoprotein (HDL) was increased markedly with statistical significance. In addition, there was an obvious improvement in t-PA activity (from 0.225 ± 0.11 to 0.457 ± 0.177 IU/ml); whereas the PAI-1 activity was decreased significantly (from 0.898 ± 0.168 to 0.533 ± 0.215 AU/ml). No significant changes were observed in plasma lipoprotein profiles and plasminogen activity in Glibenclamide receiving group. Conclusions Glimepiride can rapidly and stably improve glycemic control and lipoprotein metabolism, significantly alleviate insulin resistance and enhance fibrinolytic activity.

Comparison of Plasminogen Activator Inhibitor-1, Tissue Type Plasminogen Activator Antigen, Fibrinogen, and D-Dimer Levels in Various Age Decades in Patients With Type 2 Diabetes Mellitus and Stable Coronary Artery Disease (from the BARI 2D Trial)

Advancing age is associated with downregulation of fibrinolysis in normal subjects. This is reflected by high concentrations of plasminogen activator inhibitor-1 (PAI-1) in the blood, which has been implicated in the increasing cardiovascular morbidity and mortality with age. We sought to delineate the relation of PAI-1 to several factors, including age, gender, and ethnicity in patients with type 2 diabetes mellitus (DM) and stable coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. A total of 2,321 patients with DM and stable coronary artery disease in the BARI 2D trial were grouped by age (<50, 50 to 59, 60 to 69, and > or =70 years). Tissue-type plasminogen activator antigen, PAI-1 antigen and activity, fibrinogen, and D-dimer were quantified at baseline. The PAI-1 antigen (p <0.001) and its activity (p <0.001) and their ratios to tissue-type plasminogen activator (p <0.001) were all paradoxically lower with advancing age. In contrast, D-dimer (p <0.0001) was elevated. The fibrinogen level was greatest in the oldest age group (p = 0.01). The level of tissue-type plasminogen activator antigen did not vary with age. These age-related differences were observed primarily in men and non-Hispanic white and Asian/other participants. In conclusion, PAI-1 is inversely related to age in patients with DM and stable coronary artery disease and is associated with elevation of D-dimer, reflecting augmented fibrinolysis. The unexpected profibrinolytic state seen with advancing age and DM might reflect a protective phenomenon resulting from enhanced survival of some older patients with DM that endowed the older patients with longevity sufficient to enable them to participate in the BARI 2D trial. Targeting the factors that led to the downregulation of PAI-1 in older patients with type 2 DM might offer an attractive strategy for reducing cardiovascular risk.