Plasminogen Activator Inhibitor

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The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays

The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays

In a follow-up study, blood samples were collected from an additional 23 individuals, from whom platelet-poor (2000 g), platelet-containing (352 g) and platelet-rich plasma (200 g) were prepared and analysed as fresh-frozen and after five defrost-refreeze cycles (to deter- mine the contribution of in vitro platelet degradation). Plasminogen activator inhibitor-1 activ- ity, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasma clot lysis time, β-thromboglobulin and plasma platelet count were analysed. Platelet α-granule release (plasma β-thromboglobulin) showed a sig- nificant association with plasminogen activator inhibitor-1 antigen levels but weak associa- tions with plasminogen activator inhibitor-1 activity and a functional marker of fibrinolysis, clot lysis time. Upon dividing the study population into quartiles based on β-thromboglobulin levels, plasminogen activator inhibitor-1 antigen increased significantly across the quartiles while plasminogen activator inhibitor-1 activity and clot lysis time tended to increase in the 4 th quartile only. In the follow-up study, plasma plasminogen activator inhibitor-1 antigen was also significantly influenced by platelet count in a concentration-dependent manner. Plasma plasminogen activator inhibitor-1 antigen levels increased further after complete platelet deg- radation. Residual platelets in plasma significantly influence plasma plasminogen activator inhibitor-1 antigen levels mainly through release of latent plasminogen activator inhibitor-1 with limited effects on plasminogen activator inhibitor-1 activity, tissue plasminogen activator/
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Plasminogen activator inhibitor-1 and cardiovascular risk

Plasminogen activator inhibitor-1 and cardiovascular risk

2.1.3 Assays associated with fibrinolysis 2.1.3.1. Plasminogen activator inhibitor-1 activity PAI-1 is a plasma protein that rapidly and specifically inhibits t-PA and urokinase. Functional assays depend on the addition of excess levels of t-PA to the plasma sample and measurement of residual t-PA activity. These assays have the advantage of measuring functionally active PAI-1 but also detect other inhibitors of t-PA such as a^- antiplasmin, PAI-2, and plasminogen activator binding proteins, and have proved difficult to standardize. For instance, what constitutes an excess of added t-PA activity? How long and under what conditions should the t-PA and PAI-1 be incubated? How should the t-PA activity be measured? Should single or two-chain t- PA be used? Chandler et al (1989) standardized the measurement of PAI-1 activity in plasma using single chain t-PA at a concentration of 5 lU.ml \ incubated for 15 mins at 3T C followed by acidification and measurement of residual t-PA activity by an amidolytic method. They showed that t-PA must be added in excess, but the addition of too much reduces the assay precision as only a small fraction of the original t-PA is inhibited, whereas addition of too little t-PA will result in underestimation of PAI-1 activity. Numerous commercial kits are available for determination of PAI-1 activity.
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Plasminogen activator inhibitor type 1 deficiency

Plasminogen activator inhibitor type 1 deficiency

Plasminogen activator inhibitor, type 1 deficiency is a rare bleeding disorder whose mainstay of treatment is antifibrinolytic agents. The accurate diagnosis of this disorder remains a challenge and the develop- ment of a readily available standardized sensitive activity assay capable of differentiation between low normal levels and a true deficiency state is needed. Once available, the correlation of specific levels of deficiency with particular clinical symptoms could be established. Because this disorder results from either a qualitative or quantitative defect, an accurate PAI-1 activity assay is critical to establish the diagnosis. Also, with improved assays, the true prevalence of clinically significant PAI-1 deficiency could be determined. Although rare, PAI-1 deficiency should be considered in patients with delayed post-traumatic or postsurgical bleeding after other more common bleeding disorders have been excluded. If PAI-1 deficiency is established, then a trial of antifibrinoltyic agents should be considered. In the future, a database of patients with this disorder should be created to establish the range of clinical symptoms experienced, the genetic defects leading to a deficiency state, and the association of specific levels with clinical events.
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Association of plasminogen activator inhibitor-1 and tissue plasminogen activator with type 2 diabetes and metabolic syndrome in Malaysian subjects

Association of plasminogen activator inhibitor-1 and tissue plasminogen activator with type 2 diabetes and metabolic syndrome in Malaysian subjects

57. Hsia J, Bittner V, Tripputi M, Howard BV: Metabolic syndrome and coronary angiographic disease progression: the Women ’ s Angiographic Vitamin & Estrogen trial. Am Heart J 2003, 146:439-445. 58. Juhan-Vague I, Morange PE, Frere C, Aillaud MF, Alessi MC, Hawe E, Boquist S, Tornvall P, Yudkin JS, Tremoli E, et al: The plasminogen activator inhibitor-1 -675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH study. J Thromb Haemost 2003, 1:2322-2329.

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Association of plasminogen activator inhibitor 1 and tissue plasminogen activator with type 2 diabetes and metabolic syndrome in Malaysian subjects

Association of plasminogen activator inhibitor 1 and tissue plasminogen activator with type 2 diabetes and metabolic syndrome in Malaysian subjects

57. Hsia J, Bittner V, Tripputi M, Howard BV: Metabolic syndrome and coronary angiographic disease progression: the Women ’ s Angiographic Vitamin & Estrogen trial. Am Heart J 2003, 146:439-445. 58. Juhan-Vague I, Morange PE, Frere C, Aillaud MF, Alessi MC, Hawe E, Boquist S, Tornvall P, Yudkin JS, Tremoli E, et al: The plasminogen activator inhibitor-1 -675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH study. J Thromb Haemost 2003, 1:2322-2329.

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Role of urokinase plasminogen activator and plasminogen activator inhibitor mRNA expression as prognostic factors in molecular subtypes of breast cancer

Role of urokinase plasminogen activator and plasminogen activator inhibitor mRNA expression as prognostic factors in molecular subtypes of breast cancer

Introduction Protein and nucleic acid based markers have been introduced as prognostic and predic- tive factors in breast cancer therapy. As established clinicopathological markers are not sufficient to guide the decision whether a patient needs adjuvant chemotherapy or not, these factors mainly focus on information about the individual patient’s benefit of adjuvant chemotherapy. For this purpose, determination of antigen levels of uroki- nase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in fresh-frozen tumor tissue from primary breast cancers by a commercially available
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Effects of pitavastatin on plasminogen activator inhibitor-1 in hyperlipidemic patients

Effects of pitavastatin on plasminogen activator inhibitor-1 in hyperlipidemic patients

Notes: Bars are shown as mean ± SD. *Student’s t-test (before versus after pitavastatin treatment); **ANOVA analysis (reponders versus nonresponders). Abbreviations: LDL-C, low-density lipoprotein cholesterol; BMI, body mass index; PAI-1, plasminogen activator inhibitor; PDMP, platelet-derived microparticle; sCD40L, soluble CD40 ligand; sP-selectin, soluble P-selectin. adiponectin levels increased by one-and-a-half times or more after pitavastatin treatment, compared to their pretreatment levels. As shown in Figure 1, LDL-C levels significantly decreased in the responder and nonresponder groups. However, there were no significant differences in LDL-C levels between the groups. The plasma PDMP, sCD40L, and PAI-1 levels significantly decreased in the responder group after pitavastatin treatment compared with those in the nonresponder group. There were no sig- nificant changes in plasma levels of BMI and sP-selectin
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Picornavirus Receptor Down-Regulation by Plasminogen Activator Inhibitor Type 2

Picornavirus Receptor Down-Regulation by Plasminogen Activator Inhibitor Type 2

Therapeutic interference with virus-cell surface receptor interactions represents a viable antiviral strategy. Here we demonstrate that cytoplasmic expression of the serine protease inhibitor (serpin), plasminogen activator inhibitor type 2 (PAI-2), affords a high level of protection from lytic infection by multiple human picornaviruses. The antiviral action of PAI-2 was mediated primarily through transcriptional down-regulation of the following virus receptors: intercellular adhesion molecule 1 (ICAM-1, a cellular receptor for the major group of rhinoviruses), decay-accelerating factor (a cellular receptor for echoviruses and coxsackieviruses), and to a lesser extent the coxsackie-adenovirus receptor protein (a cellular receptor for group B coxsackievi- ruses and group C adenoviruses). Expression of related cell surface receptors, including membrane cofactor protein and the poliovirus receptor, remained unaffected. These findings suggest that PAI-2 and/or related serpins may form the basis of novel antiviral strategies against picornavirus infections and also therapeutic interventions against ICAM-1-mediated respiratory inflammation.
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Possible Role of Plasminogen Activator Inhibitor-1 in Childhood Bronchial Asthma

Possible Role of Plasminogen Activator Inhibitor-1 in Childhood Bronchial Asthma

_____________________________________________________________________________________________ ABSTRACT Background: Plasminogen activator inhibitor (PAI)-1 is the main inhibitor of the fibrinolytic system and is known to play an essential role in tissue remodeling. Chronic asthma may lead to tissue remodeling such as subepithelial fibrosis and extracellular matrix deposition in the airways. However, the role of PAI-1 in bronchial asthma is unknown. Our objective is to investigate the correlation between plasma activator inhibitor-1 and childhood bronchial asthma severity, and whether steroid medications could affect its level. The present study included 40 asthmatic children divided into 2 groups (20 patients in each); the asymptomatic group (controlled asthma) where patients were free of symptoms and the symptomatic group, where patients were suffering from acute exacerbation of their asthma and sub-classified into mild and moderate subgroups, each of 10 patients according to severity of acute exacerbation compared to 20 healthy non-asthmatic, age and sex matched. All patients were subjected to full history taking, thorough clinical examinations, peak expiratory flow rate estimation, laboratory investigating: CBC, total serum Ig E, stool analysis and estimation of plasma PAI-1. There was a significant increase of PAI-1 in all asthmatic groups in comparison to control group. The moderate subgroups (A symptomatic and symptomatic) showed highly significant increase in comparison to mild subgroups. On the other hand, there was no significant difference between mild asymptomatic and symptomatic or moderate subgroups to each other. Also there was a significant decrease in PAI-1 levels in patients receiving inhaled corticosteroids than those not receiving inhaled corticosteroids. We conclude that PAI-1 may play an important role in the pathogenesis of asthma and further studies may lead to the development of a novel therapeutic target for the treatment and prevention of asthma.
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Plasminogen activator inhibitor 1 in acute hyperoxic mouse lung injury

Plasminogen activator inhibitor 1 in acute hyperoxic mouse lung injury

Abstract Hyperoxia-induced lung disease is associated with promi- nent intraalveolar fibrin deposition. Fibrin turnover is tightly regulated by the concerted action of proteases and antipro- teases, and inhibition of plasmin-mediated proteolysis could account for fibrin accumulation in lung alveoli. We show here that lungs of mice exposed to hyperoxia overproduce plasminogen activator inhibitor-1 (PAI-1), and that PAI-1 upregulation impairs fibrinolytic activity in the alveolar compartment. To explore whether increased PAI-1 produc- tion is a causal or only a correlative event for impaired in- traalveolar fibrinolysis and the development of hyaline membrane disease, we studied mice genetically deficient in PAI-1. We found that these mice fail to develop intraalveo- lar fibrin deposits in response to hyperoxia and that they are more resistant to the lethal effects of hyperoxic stress. These observations provide clear and novel evidence for the patho- genic contribution of PAI-1 in the development of hyaline membrane disease. They identify PAI-1 as a major deleteri- ous mediator of hyperoxic lung injury. ( J. Clin. Invest. 1996.
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Thrombin induction of plasminogen activator inhibitor in cultured human endothelial cells

Thrombin induction of plasminogen activator inhibitor in cultured human endothelial cells

We have examined the effect of thrombin on the activity of plasminogen activator (PA) and plasminogen activator-inhibitor (PA-I) in medium conditioned by primary cultures of human umbili[r]

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Usefulness of plasminogen activator inhibitor-1 as a predictive marker of mortality in sepsis

Usefulness of plasminogen activator inhibitor-1 as a predictive marker of mortality in sepsis

23. Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care. 2014;2:20. 24. Koyama K, Madoiwa S, Nunomiya S, Koinima T, Wada M, Sakata A, et al. Combination of thrombin-antithrombin complex, plasminogen activator inhibitor-1, and protein C activity for early identification of severe coagulopathy in initial phase of sepsis: a prospective observational study.

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The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans

The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans

We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly ele- vated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator
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Close relationship of tissue plasminogen activator plasminogen activator inhibitor 1 complex with multiple organ dysfunction syndrome investigated by means of the artificial pancreas

Close relationship of tissue plasminogen activator plasminogen activator inhibitor 1 complex with multiple organ dysfunction syndrome investigated by means of the artificial pancreas

‡ Department of Emergency and Critical Care Medicine, Chiba University School of Medicine, Chuo-ku, Chiba-shi, Chiba, Japan Correspondence: Masami Hoshino, Department of Intensive and Critical Care Medicine, Tokyo Police Hospital, Fujimi 2-10-41, Chiyoda-ku, Tokyo 102, Japan. Tel: +81 3 3263 1371; fax: +81 3 3239 7856; e-mail: noel2000@aioros.ocn.ne.jp AP = artificial pancreas; AT-III = antithrombin III; BG = blood glucose level; DIC = disseminated intravascular coagulation; ECA = endothelial cell activation; ECI = endothelial cell injury; GT = glucose tolerance; MODS = multiple organ dysfunction syndrome; mMOF = modified multiple organ failure; NIDDM = noninsulin-dependent diabetes mellitus; PAI-1 = plasminogen activator inhibitor-1; PLT = platelet count; PT = prothrombin time;
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Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

18. Tofler GH, Massaro J, O'Donnell CJ, Wilson PW, Vasan RS, Sutherland PA, Meigs JB, Levy D, D'Agostino RB, Sr. Plasminogen activator inhibitor and the risk of cardiovascular disease: The framingham heart study. Thrombosis research. 2016;140:30-35 19. Huang J, Sabater-Lleal M, Asselbergs FW, Tregouet D, Shin SY, Ding J, Baumert J, Oudot-Mellakh T, Folkersen L, Johnson AD, Smith NL, Williams SM, Ikram MA, Kleber ME, Becker DM, Truong V, Mychaleckyj JC, Tang W, Yang Q, Sennblad B, Moore JH, Williams FM, Dehghan A, Silbernagel G, Schrijvers EM, Smith S, Karakas M, Tofler GH, Silveira A, Navis GJ, Lohman K, Chen MH, Peters A, Goel A, Hopewell JC, Chambers JC, Saleheen D, Lundmark P, Psaty BM, Strawbridge RJ, Boehm BO, Carter AM, Meisinger C, Peden JF, Bis JC, McKnight B, Ohrvik J, Taylor K, Franzosi MG, Seedorf U, Collins R, Franco-Cereceda A, Syvanen AC, Goodall AH, Yanek LR, Cushman M, Muller- Nurasyid M, Folsom AR, Basu S, Matijevic N, van Gilst WH, Kooner JS, Hofman A, Danesh J, Clarke R, Meigs JB, Consortium D, Kathiresan S, Reilly MP, Consortium CA, Klopp N, Harris TB, Winkelmann BR, Grant PJ, Hillege HL, Watkins H, Consortium CD, Spector TD, Becker LC, Tracy RP, Marz W, Uitterlinden AG, Eriksson P, Cambien F, Consortium C, Morange PE, Koenig W, Soranzo N, van der Harst P, Liu Y, O'Donnell CJ, Hamsten A. Genome-wide association study for circulating levels of pai-1 provides novel insights into its regulation. Blood. 2012;120:4873-4881 20. Nikpay M, Goel A, Won HH, Hall LM, Willenborg C, Kanoni S, Saleheen D, Kyriakou T, Nelson CP, Hopewell JC, Webb TR, Zeng L, Dehghan A, Alver M, Armasu SM, Auro K, Bjonnes A, Chasman DI, Chen S, Ford I, Franceschini N, Gieger C, Grace C, Gustafsson S, Huang J, Hwang SJ, Kim YK, Kleber ME, Lau KW, Lu X, Lu Y, Lyytikainen LP, Mihailov E, Morrison AC, Pervjakova N, Qu L, Rose LM, Salfati E, Saxena R, Scholz M, Smith AV, Tikkanen E, Uitterlinden A, Yang X, Zhang W, Zhao W, de Andrade M, de Vries PS, van Zuydam NR, Anand SS, Bertram L, Beutner F, Dedoussis G, Frossard P, Gauguier D, Goodall AH, Gottesman O, Haber M, Han BG, Huang J, Jalilzadeh S,
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Peptide mediated inactivation of recombinant and platelet plasminogen activator inhibitor 1 in vitro

Peptide mediated inactivation of recombinant and platelet plasminogen activator inhibitor 1 in vitro

J Clin Invest. 1995;95(5):2416-2420. https://doi.org/10.1172/JCI117937. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator, is an important regulator of the blood fibrinolytic system. Elevated plasma levels of PAI-1 are associated with thrombosis, and high levels of PAI-1 within platelet-rich clots contribute to their resistance to lysis by t-PA.

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Development and optimization of the methods for determining activity of plasminogen activator inhibitor-1 in plasma

Development and optimization of the methods for determining activity of plasminogen activator inhibitor-1 in plasma

Важными показателями патологических процессов принято считать активность и ко- личество ингибитора активатора плазмино- гена 1-го типа (plasminogen activator inhibitor, РАІ-1), поскольку его количество в плазме воз- растает при остром инфаркте миокарда, зло- качественных новообразованиях, сахарном диабете и т.д. Работа посвящена разработке и оптимизации методов определения PAI-1, ко- торые могут быть использованы в лабораторно- клинической практике. Предложена модифи- кация метода COATEST PAI для определения ингибиторной активности с использованием хромогенного субстрата S2251, согласно с ко- торой мы заменили фрагменты бромцианового расщепления фибриногена человека на desAB- фибрин быка. Разработан также метод опре- деления активности ингибитора с использова- нием фибриновых пленок, в котором фиб рин является одновременно и стимулятором реак- ции активации, и субстратом. использование фибрина, природного субстрата плазмина, обеспечивает высокую специфичность метода и позволяет избежать перекрестной реакции с другими энзимами плазмы.
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Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity

Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity

Indirect ELISA for plasminogen activator inhibitor type 1 Indirect ELISA was used for the recombinant mouse PAI-1 protein measurements. Cells were treated with a combination of LPS (100 ng/ml) and IFN-γ (50 U/ml) for 24 hours. The stimulation was performed under serum-free conditions. The conditioned medium was then collected, and separated by centrifugation at 400 g for 5 minutes to remove cell debris. The wells of micro- titer plates were coated with conditioned medium over- night (diluted 1:1 in 50 mmol/l carbonate buffer, pH 9.6; 100 μl/well in triplicate wells). Plates were washed with PBS plus 0.1% Triton X-100 and blocked with PBS plus 5% BSA for 1 hour. Plates were emptied, and any remaining liquid was tapped out onto dry paper towels. Rabbit polyclonal anti-mouse PAI-1 antibody was added (1 μg/ml; 100 μl per well) and incubated for 5 hours. Plates were washed three times with PBS-T to remove unbound antibody. Horseradish peroxidase-labeled anti- rabbit IgG was added (1:1000 dilution; 100 μl per well) and incubated for 1 hour. Plates were washed three times with PBS-T and developed by the addition of 100 μl of tetramethylbenzidene peroxide-based substrate solution (R&D Systems). The recombinant mouse PAI-1 protein was used as a standard.
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Coordinated induction of plasminogen activator inhibitor 1 (PAI 1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition

Coordinated induction of plasminogen activator inhibitor 1 (PAI 1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition

D J Pinsky, … , D J Loskutoff, D M Stern J Clin Invest. 1998;102(5):919-928. https://doi.org/10.1172/JCI307. Oxygen deprivation, as occurs during tissue ischemia, tips the natural anticoagulant/procoagulant balance of the endovascular wall to favor activation of coagulation. To investigate the effects of low ambient oxygen tension on the fibrinolytic system, mice were placed in a hypoxic environment with pO2 < 40 Torr. Plasma levels of plasminogen activator inhibitor-1 (PAI-1) antigen, detected by ELISA, increased in a time- dependent fashion after hypoxic exposure (increased as early as 4 h, P < 0.05 vs. normoxic controls), and were accompanied by an increase in plasma PAI-1 activity by 4 h (P < 0.05 vs. normoxic controls). Northern analysis of hypoxic murine lung demonstrated an increase in PAI-1 mRNA compared with normoxic controls; in contrast, transcripts for both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) decreased under hypoxic conditions. Immunocolocalization studies identified macrophages as the predominant source of increased PAI-1 within hypoxic lung. Using a transformed murine macrophage line, striking induction of PAI-1 transcripts occurred under hypoxic conditions, due to both increased de novo transcription as well as increased mRNA stability. Consistent with an important role of the fibrinolytic system in hypoxia-induced fibrin accumulation, PAI- 1 +/+ mice exposed to hypoxia exhibited increased pulmonary fibrin deposition based upon a fibrin immunoblot, intravascular fibrin identified by immunostaining, and increased
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Coagulopathy After Cardiac Surgery May Be Influenced by a Functional Plasminogen Activator Inhibitor Polymorphism

Coagulopathy After Cardiac Surgery May Be Influenced by a Functional Plasminogen Activator Inhibitor Polymorphism

Ross McManus, PhD†‡ Thomas Ryan, MB, FFARCSI* BACKGROUND: Cytokine-mediated inflammation and coagulopathy may occur after cardiac surgery. In this study we investigated the temporal pattern of plasminogen activator inhibitor-1 (PAI-1) gene expression after cardiac surgery and its relation with PAI genotype, and obtained preliminary data regarding its relation to perioperative morbidity.

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