Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Semen specimens from four groups of patients were evaluated for coagulation and fibrinolysis factors: a group of patients with infertile semen and involuntary childlessness (n = 35), a group with fertile semen and involuntary childlessness (n = 39), a group with fertile semen and proven fertility before vasectomy (n = 34) and a group with infertile semen after vasectomy (n = 147). The third patient group with proven fertility before vasectomy was considered as a control group. Only small amounts of fibrinogen, factor VIII:c, plasminogen, antithrombin III, fibrin monomers and plasminogen activator inhibitor-1 were detected in seminal plasma. The thrombin-antithrombin III, D-dimer and tissue plasminogen activator regular concentrations were measured and the D-dimer/thrombin-antithrombin III ratios calculated. The reference ranges were assessed and the quantities were compared in the different patient groups. Significant differences were demonstrated between the prevasectomy group (= control group) and both the postvasectomy and the infertility groups with respect to D-dimer and D-dimer/thrombin-antithrombin III ratio. We conclude that both coagulation and fibrinolysis play a part in coagulum formation and liquefaction of seminal plasma. The balance between coagulation and fibrinolysis (expressed as D-dimer/thrombin-antithrombin III ratio) was significantly different between the control group and the three patient groups. The coagulation/fibrinolysis balance was impaired in the semen from post vasectomy patients and from those with involuntary childlessness and the D-dimer/thrombin-antithrombin III ratios in both these patient groups were very similar.
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PMID:Coagulation and fibrinolysis markers in seminal plasma of patients under evaluation for involuntary childlessness. 144 60

OBJECTIVE -- Postsurgical adhesion formation remains an unpredictable complication in operative surgery but is of special importance to the infertility surgeon. Recent reports on recombinant tissue plasminogen activator (tPA) and oxidized regenerated cellulose (ORC) have been promising. The present study set forth to verify these results and to explore possible synergistic effects of these two agents. METHODS -- Four groups of five rats each were subjected to a standardized caecal crush model and treated with ORC, tPA, a combination of these two or nothing. RESULTS -- The ORC group had significantly more postoperative adhesions than the other two groups (P < .05). This adhesion-promoting effect was mitigated when ORC was combined with tPA. The tPA group did not differ from the control group. CONCLUSIONS -- ORC and tPA were unable to decrease adhesion formation in rats with the current type of lesion. Nevertheless, tPA mitigated the adhesion-increasing effect of ORC. These findings underline the need for more research to establish the antiadhesion properties of ORC and tPA and lend support to the notion that all adhesions are not alike.
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PMID:Counteracting postsurgical adhesions--the effect of combining oxidized regenerated cellulose and tissue plasminogen activator. 759 56

The increased incidence of postoperative adhesions and their complications have refocused attention on our understanding of adhesions, their clinical consequences and prevention. Postsurgical adhesions have four major negative impacts on health care outcomes. First, adhesions cause significant morbidity, including intestinal obstruction, infertility and pelvic pain. Second, adhesions are associated with multiple surgical complications. Third, these complications lead to greater surgical workload and utilization of hospital and other health care resources. Fourth, all these negative impacts result in significant economic burden to society. The complexities of adhesion formation and limitations in their understanding and research have hampered the development of satisfactory preventive treatments. Adhesions are highly differentiated, formed through an intricate process and associated with a complex organ, the peritoneum. The surface lining of the peritoneum is the key site in adhesion formation and prevention. Two unique properties of the peritoneal surface play key roles in these processes: its delicacy and its uniform, relatively rapid rate of re-epithelialization, irrespective of the size of injury. A suitable barrier that separates damaged peritoneal surfaces for the entire five to seven days of re-epithelialization is likely to prove effective in reducing adhesion formation. Postsurgical peritoneal repair begins with coagulation, which releases a variety of chemical messengers that bring about a cascade of events. Some of the principal cellular elements in this cascade are leukocytes, including polymorphonuclear neutrophils and macrophages, mesothelial cells, and fibrin. Following surgical injury, macrophages exhibit increased phagocytic, respiratory burst and secretory activity, and after day 5, are the major component of the leukocyte population. Macrophages also recruit new mesothelial cells onto the surface of the injury. These cells form small islands throughout the injured area which proliferate into sheets of mesothelial cells and accomplish re-epithelialization, usually five to seven days after surgical injury. The progenitor to adhesions is the fibrin gel matrix which develops in several steps. These include the formation and insolubilization of fibrin polymer and its interaction with fibronectin and a series of amino acids. Protective fibrinolytic enzyme systems of the peritoneal mesothelium, such as the tissue plasminogen activator (tPA) system, can remove the fibrin gel matrix. However, surgery dramatically diminishes fibrinolytic activity. This occurs in at least two ways: first, by increasing levels of plasminogen activator inhibitors and second, by reducing tissue oxygenation. Peritoneal re-epithelialization and adhesion formation thus can be seen as alternative pathways following peritoneal injury. The pivotal events determining the pathway are the apposition of two damaged surfaces and the extent of fibrinolysis. Development of strategies to separate damaged peritoneal surfaces and to foster an appropriate degree of fibrinolysis appears to be among the most promising avenues of adhesion prevention research. Hopefully, these efforts will lead to adhesion-free peritoneal healing following abdominal surgery.
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PMID:Biochemical events in peritoneal tissue repair. 907 47

Adhesions, which occur after 67% to 93% of abdominal operations, represent a major clinical problem, resulting in intestinal obstruction, infertility, and pain and incurring considerable economic costs. The magnitude and seriousness of the problem of adhesions have been underappreciated. Moreover, efforts to prevent or reduce adhesions largely have been unsuccessful, hindered by their empirical basis, the lack of good predictive animal models, and the biochemical complexities of adhesiogenesis. The two major strategies for adhesion prevention or reduction are adjusting surgical technique and applying adjuvants. Modifications in technique that all surgeons should implement include minimizing the invasiveness of surgery, minimizing surgical trauma, such as ischemia from peritoneal suturing, and avoiding the introduction of foreign material, e.g., starch glove powder, into the body. Given the adhesiogenic nature of peritoneal repair, however, improvements in surgical technique alone will help decrease but not prevent adhesion formation. Adjuvant therapy is necessary. Adjuvants fall into two main categories, drugs and barriers. Nonsteroidal anti-inflammatory drugs have shown questionable clinical efficacy, possibly because of difficulties in drug delivery. Corticosteroids, alone or with antihistamines, also have had equivocal clinical results and may be immunosuppressive and delay wound healing. Experimentally, fibrinolytics such as tissue plasminogen activator (tPA), administered systemically or intraperitoneally (i.p.), have demonstrated conflicting results and hemorrhagic complications. However, recently, tPA, administered topically in a carboxymethylcellulose (CMC) gel, has been effective in reducing and preventing adhesions in rabbits. Phosphatidylcholine, given i.p. or orally, also has shown promise in animal studies. Barriers, by separating traumatized surfaces for the critical first five to seven days of peritoneal re-epithelialization, are useful adjuvants, and include macromolecular solutions and mechanical devices. Dextran, a macromolecular solution, has been studied widely, but has not demonstrated consistent clinical efficacy and has been largely abandoned as an anti-adhesion barrier. A newly developed hyaluronic acid-phosphate-buffered saline solution applied intraoperatively to protect peritoneal surfaces from indirect surgical trauma effectively and safely reduced adhesions in a large multicenter study of women undergoing gynecological laparotomy. Three recently developed mechanical barriers also have demonstrated clinical progress in adhesion prevention. A bioresorbable membrane consisting of hyaluronic acid and CMC has gained regulatory approval for clinical use in both general and gynecological surgery following demonstration of efficacy and safety in reducing adhesions. A barrier made of expanded polytetrafluoroethylene and another developed from oxidized regenerated cellulose are currently available for gynecological surgery. With continued research, new and improved approaches hopefully will become available to prevent adhesion formation.
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PMID:Adhesions: preventive strategies. 907 50

Protein C inhibitor (PCI) has been found in seminal plasma and is considered to protect intact surrounding cells and seminal plasma proteins from possible proteolytic damage. In the present study, we showed that although the antigenic levels of PCI in two seminal plasma samples from patients with infertility were normal or slightly elevated, their inhibitory activities toward urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) were absent. In contrast, uPA and tPA proteolytic activities in these two samples were 20-60-fold higher than that from normal volunteers. A time-course analysis of PCI-uPA complex formation showed that >80% of the complex had been formed within 15 min in normal seminal plasma in the presence of heparin, compared with the total complex formed after 150 min incubation, whereas no response to heparin stimulation was observed in the assays with the two patient samples. Similarly, >90% of PCI-tPA complex was formed after 30 min of heparin stimulation in normal seminal plasma but no response was observed in the two patient samples. Kinetic assays of PCI inhibitory function in the presence of activated protein C (APC) showed that PCI inhibitory activity in the two patient samples was absent and not stimulated by heparin. Western blotting also showed that most of the intact PCI molecules, in normal samples, formed complexes with either uPA or tPA but there was no complex formed in one of the two patient samples and very little complex was observed in the other, suggesting that PCI in the two patient samples is inactive. These results suggest that the presence of functionally inactive PCI in seminal plasma may be associated with infertility.
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PMID:Functionally inactive protein C inhibitor in seminal plasma may be associated with infertility. 1034 Sep 97

Intra-abdominal adhesion formation is a major complication of serosal repair following surgery, ischaemia or infection, leading to conditions such as intestinal obstruction and infertility. It has been proposed that the persistence of fibrin, due to impaired plasminogen activator activity, results in the formation of adhesions between damaged serosal surfaces. This study aimed to assess the role of fibrinolysis in adhesion formation using mice deficient in either of the plasminogen activator proteases, tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA). We hypothesize that, following serosal injury, mice with decreased peritoneal fibrinolytic activity will be more susceptible to adhesion formation. Adhesion formation was induced in tPA- and uPA-deficient and wild-type mice following either surgical trauma to the serosa with haemorrhage and acute or chronic intraperitoneal inflammation. Adhesion formation was assessed from 1 to 4 weeks post-injury. Mice deficient in tPA were more susceptible to adhesion formation following both a surgical insult and a chronic inflammatory episode compared with uPA-deficient and wild-type mice. In addition, the time of maximal adhesion formation varied depending on the nature of the initial insult. It is proposed that the persistence of fibrin due to decreased tPA activity following surgery or chronic inflammation plays a major role in peritoneal adhesion formation.
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PMID:Role of plasminogen activators in peritoneal adhesion formation. 1202 39

In order to describe potential hypofibrinolytic tendencies in young (< 35 years) polycystic ovary syndrome (PCOS) patients, we studied plasminogen activator inhibitor (PAI-1) system components in women without laboratory evidence of hyperinsulinism or hyperandrogenism. The study was a prospective, observational comparison and took place in a major urban infertility referral center. Age, body mass index, ovulatory status, selected androgen levels, fasting insulin and plasma lipids were measured in subjects with PCOS (n = 39) and normal control subjects (n = 20). Women with PCOS had higher mean serum total testosterone and androstenedione levels compared with controls (56.4 versus 40.3 ng/dl, p = 0.03, and 179 versus 133 microg/ml, p = 0.03, respectively). Mean fasting insulin levels were higher among PCOS women (p < 0.01) and were strongly correlated with PAI-1 antigen (Ag) (r = 0.46), PAI-1 activity (r = 0.43), and tissue plasminogen activator (t-PA) (r = 0.5). Correlations were evident in both PCOS and control subjects. Mean PAI-1 Ag, PAI-1 activity, and t-PA levels were significantly elevated (p = 0.003, 0.001, and 0.001, respectively) in PCOS. ANOVA was performed to control for insulin effect; a trend toward elevated PAI-1 in PCOS persisted but was no longer statistically significant (p = 0.24). PAI-1 activity elevation remained in PCOS women with mean fasting insulin levels < 10 mIU/ml (p = 0.02), yet the difference became less significant when insulin was controlled (p = 0.38). Although these data confirm known associations between insulin and PAI-1 derangements, this is the first study to quantify discrete PAI-1 elevations that persist in the setting of PCOS even with normal or low ambient insulin levels. Additional prospective studies are needed to determine whether this altered PAI-1 state is associated with a clinically important hypofibrinolytic condition and subsequent poor reproductive outcome.
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PMID:Absence of profound hyperinsulinism in polycystic ovary syndrome is associated with subtle elevations in the plasminogen activator inhibitor system. 1285 31

Thrombophilic disorders and hypofibrinolysis were demonstrated to be risk factors in a majority of women with recurrent pregnancy loss (RPL) and infertility. We investigated the association of FV G1691A mutation, F II G20210A gene polymorphism (PM), 4G/5G PAI-1 and Alu I/D tPA PM in 32 women with infertility and 49 women with at least 2 unexplained early abortions. FV Leiden mutation was significantly more common in women with RPL (10%, p = 0.02) and infertility (19%, p = 0.0005) compared with controls (2%). PAI-1 4G PM and t-PA Alu I PM, alone or in combination, were not associated with RPL or infertility. 9/49 women with RPL showed coagulation disorders with heterozygous FV Leiden mutation (5), FXII (1), protein C (1) or protein S (2) deficiency. However, due to the small number of patients studied, no definite conclusion can be drawn.
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PMID:Recurrent pregnancy loss and its relation to FV Leiden, FII G20210A and polymorphisms of plasminogen activator and plasminogen activator inhibitor. 1517 Mar 93

The distribution of total fibrinolytic activity in seminal plasma, as well as specific tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), and plasminogen activator inhibitor (PAI), has been studied using antigen and activity techniques in 170 ejaculates of men attending for assessment because of infertility without genital urinary pathology. Among these 170 patients, 18 showed oligoasthenoteratospermia, 28 showed azoospermia, and 124 showed normozoospermia. The seminal values were 50 times higher (262 to 289 ng/mL in antigen and 179 to 199 x 10 (3) IU/L for activity) than values in blood for t-PA and 15 times higher than values in blood for u-PA (18.4 to 26 ng/mL and 1.5 to 2.4 IU/mL, respectively). There was no correlation between the two levels in antigen or activity, but a higher concentration was observed in all first fractions from split ejaculates measurements. Moreover, t-PA was significantly lower in semen with abnormal liquefaction compared with semen exhibiting normal liquefaction. Zymography confirms the active forms. PAI was absent or at the detection limit for normozoospermia, whereas patients with oligoasthenoteratospermia or azoospermia showed high PAI antigen and activity levels. These data demonstrate that seminal PA activity may be related to sperm fertilizing capacity.
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PMID:Human seminal plasma fibrinolytic activity. 1725 86

The fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiological and pathophysiological functions in several processes, such as haemostatic balance, tissue remodeling, tumor invasion, angiogenesis and reproduction. The main enzyme of the plasminogen activator system is plasmin, which is responsible for the degradation of fibrin into soluble degradation products. The activation of plasminogen into plasmin is mediated by two types of activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). The activity of both is regulated by specific plasminogen activator inhibitors (PAIs). There are 3 types of PAIs described so far but the most important fibrinolytic inhibitor in vivo is PAI type 1 (PAI-1). Among others, the presence of metabolic syndrome and the -675 4G/5G promoter polymorphism are known to be modulators of PAI-1 levels. Besides their fibrinolytic profile, plasmin and plasminogen activators are implicated in tissue proliferation and cellular adhesion, as they can proteolytically degrade the extracellular matrix and regulate the activation of both growth factors and matrix metalloproteinases. By all these means, the fibrinolytic system is also involved in physiological processes, and in pathological situations such as thrombosis, arteriosclerosis, endometriosis and cancer. PAI 1 has been studied in different settings with thrombotic pathophysiology, such as coronary artery disease and ischaemic stroke. Controversial results have been published and concerns about study designs or presence of confounders have been claimed to be responsible of them. Recently, its involvement in adverse thrombotic events related to the modern drug-eluting coronary stents has renewed the interest of its study. PAI-1 also plays an important role in signal transduction, cell adherence, and migration. Indeed, studies of several types of cancers, including breast cancer, have shown that increased uPA and PAI-1 levels are associated with aggressive tumor behavior and poor prognosis. Endometriosis is defined by the presence of endometrial glands and stroma outside the uterus with marked ability to attach and invade the peritoneum. It is one of the most frequent benign gynecological diseases that affect women with pelvic pain or infertility during their reproductive age. Immune system disorders, genetic predisposition, altered peritoneal environment and endometrial alterations are believed to increase the susceptibility to endometriosis. The plasminogen activator system may be involved in this process, where local extracellular proteolysis plays a crucial role. Altered expression of several components of the fibrinolytic system in both eutopic and ectopic endometrium and peritoneal fluid of women with the disease has been implicated not only in the onset, but also in the progression of the endometriotic lesions.
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PMID:Fibrinolysis: the key to new pathogenetic mechanisms. 1847


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