Increased PAI-1 plasma levels and risk of death from dengue: no association with the 4G/5G promoter polymorphism
© Mairuhu et al; licensee BioMed Central Ltd. 2005
Received: 17 March 2005
Accepted: 07 November 2005
Published: 07 November 2005
Dengue virus infected patients have high plasminogen activator inhibitor type I (PAI-1) plasma concentrations. Whether the insertion/deletion (4G/5G) polymorphism in the promotor region of the PAI-1 gene is associated with increased PAI-1 plasma concentrations and with death from dengue is unknown. We, therefore, investigated the relationship between the 4G/5G polymorphism and PAI-1 plasma concentrations in dengue patients and risk of death from dengue.
A total of 194 patients admitted to the Dr. Kariadi Hospital in Semarang, Indonesia, with clinical suspected severe dengue virus infection were enrolled. Blood samples were obtained on day of admission, days 1, 2 and 7 after admission and at a 1-month follow-up visit. Plasma concentrations of PAI-1 were measured using a sandwich ELISA kit. The PAI-1 4G/5G polymorphism was typed by allele-specific PCR analysis.
Concentrations of PAI-1 on admission and peak values of PAI-1 during admission were higher than the values measured in healthy controls. Survival was significantly worse in patients with PAI-1 concentrations in the highest tertile (at admission: OR 4.7 [95% CI 0.9–23.8], peak value during admission: OR 6.3 [95%CI 1.3–30.8]). No association was found between the PAI-1 4G/5G polymorphism, and PAI-1 plasma concentrations, dengue disease severity and mortality from dengue.
These data suggest that the 4G/5G polymorphism has no significant influence on PAI-1 concentrations in dengue virus infected patients and is not associated with the risk of death from dengue. Other factors contributing to the variability of PAI-1 plasma concentrations in patients with dengue need to be explored.
Dengue is the most prevalent viral disease transmitted by arthropod vectors worldwide . An estimated 50–100 million cases of dengue fever and 500.000 cases of dengue haemorrhagic fever resulting in around 24.000 deaths occur annually depending on epidemic activity [1, 2]. At present, almost 30% of the world population is at risk for dengue virus infection and it is expected that this number will increase substantially as transmission spreads to other yet unaffected geographic regions . The viruses are transmitted to humans through infected mosquitoes, and may induce clinical manifestations ranging from a mild, uncomplicated febrile illness to the more severe dengue haemorrhagic fever and dengue shock syndrome. Increased vascular permeability is thought to be central in the pathogenesis of dengue haemorrhagic fever and dengue shock syndrome, since it results in the loss of plasma from the vascular compartment, which may give rise to shock in severe cases. Bleeding manifestations are believed to result from thrombocytopenia and thrombocytopathia, but increasing evidence suggests an important role for other abnormalities in the coagulation and fibrinolytic systems .
Nearly all patients suffering from dengue haemorrhagic fever show some evidence of a deranged coagulation system, but coagulation abnormalities are most marked in dengue shock syndrome patients . The activity of the fibrinolytic system is amongst others regulated by plasminogen activator inhibitor type I (PAI-1), of which levels may greatly increase during acute phase reactions. Indeed, levels of PAI-1 are high in particular in dengue shock syndrome patients with an adverse clinical outcome [6, 7]. A single base pair insertion/deletion (4G/5G) polymorphism in the promotor region of the PAI-1 gene has been associated with increased plasma concentrations of PAI-1 and with the development of shock and death after infection with Neisseria meningitides [8, 9]. We therefore investigated whether in dengue virus infected patients increased PAI-1 levels are associated with a greater risk of death from dengue and whether the 4G/4G genotype contributes to these higher levels.
Patients were selected from two observational studies conducted in the Dr. Kariadi Hospital in Semarang, Indonesia. In the first study, performed from 1996 to 1997 at the paediatric intensive care unit, a total of 50 patients with a clinical diagnosis of suspected dengue shock syndrome were studied. Blood samples were obtained from these patients on day of admission and on days 1, 2 and 7 after admission. The study protocol and the results of the measurement of PAI-1 plasma levels have been described previously . The second study was performed from 2001 to 2003 at the paediatric intensive care unit and the paediatric ward. Patients, aged 3 to 14 years, admitted to the hospital with a clinical diagnosis of suspected dengue shock syndrome or with a clinical diagnosis of suspected dengue haemorrhagic fever were included. Demographic data, medical history, physical examination findings and subsequent progress for each patient were recorded on a standard data form. Blood samples were obtained on day of admission, days 1, 2 and 7 after admission and at a 1-month follow-up visit. A formal classification, according to WHO criteria , using all available clinical and laboratory data, was done after completion of both studies. If dengue virus infected patients did not meet the criteria for dengue haemorrhagic fever or dengue shock syndrome, they were considered to suffer from dengue fever. The controls were healthy school-aged children who had no history of dengue haemorrhagic fever or dengue shock syndrome and originated from the same geographical area as the cases.
All blood samples were centrifuged within 1–2 hours after retrieval at 15°C for 20 minutes at 1600*g. Plasma was separated, stored at -80°C and assayed batch-wise in the Netherlands after transportation on dry ice. Since coagulation test results are affected by poor sample quality, only test results of samples with no visible haemolysis or clot formation were included in this analysis. Plasma concentrations of PAI-1 were measured using two separate assays. A sandwich ELISA kit that has been described by de Boer et al , was used in the 1996–1997 study. In the second study a commercially available sandwich ELISA kit (Imulyse, Biopool, Sweden) was used. Genomic DNA from patients was prepared either from EDTA whole blood by means of a salting out method as described elsewhere or in case only plasma samples were available with use of the Invisorb® Spin Cell Mini Kit (Invitek GmbH, Berlin, Germany) . The insertion/deletion (4G/5G) polymorphism in the promotor region of the PAI-1 gene was typed by allele-specific PCR and RFLP analysis . The ethics committee of the Dr. Kariadi Hospital approved all clinical and laboratory aspects of both studies. Blood samples were taken from patients and controls provided that a parent or legal guardian gave informed consent.
Paired blood samples from both studies were tested for serologic evidence of acute dengue infection. A commercially available capture and indirect ELISA (Focus Technologies, Cypress, Calif., USA) was used for the detection of dengue virus specific IgM and IgG antibodies respectively. This was performed according to the procedures described by the manufacturer . For some patients, a definitive serodiagnosis was not possible because no convalescent sample was obtained. Detection of dengue antigen and RNA was attempted in these cases using a dot blot immunoassay and a dengue serotype specific revere transcriptase PCR respectively . Patients with serologic evidence of acute dengue infection, a positive dot blot and/or positive PCR were considered to have confirmed dengue virus infection. Those with definite negative serology and/or a well-substantiated alternative clinical diagnosis were classified as not dengue. In the absence of a well-substantiated alternative clinical diagnosis and with inconclusive serology patients were classified as indeterminate.
Categorical data are expressed as numbers and frequencies, and were compared by means of χ2 analysis. Continuous data are expressed as medians with corresponding interquartile ranges and were compared by means of the Kruskal Wallis test. Since PAI-1 plasma levels were measured using two different assays, the nonparametric regression procedure of Passing and Bablok was used to compare these two methods and to validate recalculation of one of the datasets to pool the data . For this purpose, 39 samples were analysed with both assays. The Passing and Bablok regression equation resulting from this comparison is given in the Results section, together with the 95% confidence intervals for the estimates of slope and intercept. PAI-1 plasma levels obtained from the 1996–1997 cohort were converted using the regression equation. We subsequently divided PAI-1 plasma levels on admission and peak PAI-1 plasma levels during admission into tertiles of similar size. Odds ratios and the corresponding 95% confidence intervals (95% CI) were estimated by cross-tabulation using the lowest tertile as reference category. To determine the association between PAI-1 concentration and mortality independent of age, sex, year project and plasminogen activator inhhibitor-1 polymorphism, we used logistic regression analyses. A P-value ≤ 0.05 was considered to indicate statistical significance. Analyses were performed using SPSS 11.0.1. Method comparison was performed using Analyse-it Clinical Laboratory statistics module version 1.62 for Microsoft Excel.
Of 233 enrolled patients with suspected dengue haemorrhagic fever or dengue shock syndrome admitted to the paediatric intensive care unit and the paediatric ward of the Dr. Kariadi Hospital, 202 (87%) were confirmed to have acute dengue, 3 (1%) were categorised as definitely not dengue and 28 (12%) as indeterminate. When a formal classification using the criteria set by the WHO was performed, 106 (52%) were classified as having dengue shock syndrome, 76 (38%) as having dengue haemorrhagic fever and 20 (10%) as having dengue fever. Nineteen of 202 patients with confirmed dengue (9%) died during follow up.
Clinical characteristics and laboratory findings
Age, median (IQR), years
Male sex, n (%)
Duration of symptoms, median (range), days
Systolic blood pressure, median (IQR), mmHg
Pulse pressure <20 mmHg, n (%)
Spontaneous bleeding, n (%)
Haematocrit, median (IQR), %
Platelet count, median (IQR), cells *103/mm3
Clinical outcome of dengue virus infected patients classified by PAI-1 genotype
Dengue disease severity and PAI-1 genotype
Relation between PAI-1 plasma levels and disease severity°
Mortality risk for plasminogen activator-1 plasma levels.*
Number of patients
Number of deaths
OR (95% CI)
ORadj (95% CI)°
Value at admission
Maximum value during admission
This study was undertaken to investigate the relationship between PAI-1 plasma concentrations and clinical outcome of dengue virus infections, and to establish whether PAI-1 plasma concentrations in dengue virus infected individuals are associated with the 4G/5G promotor polymorphism in the PAI-1 gene. We and others have previously found increased PAI-1 plasma concentrations in patients with severe dengue in particular in those with a poor clinical outcome [5, 7]. Since a genetic predisposition to produce high PAI-1 plasma concentrations appears to be associated with poor clinical outcome in Neisseria meningitides infections [8, 9], we hypothesised that dengue virus infected individuals carrying the 4G/4G genotype have higher PAI-1 plasma concentrations and are therefore at increased risk of death. Consistent with previous studies, we found increased PAI-1 concentrations in dengue virus infected individuals. However, PAI-1 plasma concentrations were not related to dengue disease severity, but were significantly associated with death from dengue. No significant association between PAI-1 plasma concentrations and carriage of the 4G/4G genotype was observed. The frequencies of the three genotypes between survivors and non-survivors, and between patients with different disease severities were not different. These findings suggest that increased PAI-1 plasma concentrations, and dengue disease severity and mortality are not dependent on the 4G polymorphism in the PAI-1 gene in this population.
An increased risk of death in dengue virus infected patients with high PAI-1 plasma concentrations adds to findings of PAI-1 levels being able to predict lethality in patients with bacterial sepsis in a very sensitive way [16–20]. One of the primary roles of PAI-1 in vivo is to inhibit tissue-type plasminogen activator, the major proteolytic activator of plasminogen [21, 22]. By inhibiting fibrinolytic activity, increased PAI-1 concentrations may contribute to a procoagulant state leading to an increased deposition of fibrin and formation of microthrombi with subsequent multiorgan failure and death. A variety of cells, including endothelial cells, hepatocytes and platelets, synthesize and secrete PAI-1 in response to inflammatory stimuli such as interleukin-1 and tumour necrosis factor [10, 22–24]. The release of these inflammatory mediators by monocytes and T lymphocytes activated by dengue virus may well contribute to the over-production of this inhibitor of fibrinolysis [25–27]. Dawson and colleagues showed that the common insertion/deletion (4G/5G) polymorphism in the promotor region of the PAI-1 gene affects the response of the gene to acute phase stimuli . The 4G allele produced six times more mRNA than the 5G allele in response to interleukin-1 . Eriksson and colleagues, however, were unable to reproduce these findings and based on their study results they concluded that the insertion/deletion (4G/5G) polymorphism is not related to an allele-specific response to interleukin-1 . Instead, they found that the insertion/deletion (4G/5G) polymorphism influences basal PAI-1 transcription only .
Apparently other underlying mechanisms not related to the 4G/5G polymorphism must be involved in the increase in PAI-1 levels found in dengue virus infected individuals. This might include clearance impairment rather than or in addition to stimulation of synthesis. It is interesting to note that PAI-1 is cleared from the circulation by the liver . Indeed in patients with severe liver disease, PAI-1 has been shown to be increased as a result of a decrease in hepatic clearance [30, 31]. Since hepatic dysfunction is a relatively common finding in severe dengue virus infections, it is possible that a less efficient clearance contributes to increased PAI-1 levels in dengue virus infected individuals [32–34]. Previous studies investigated factors that could potentially influence PAI-1 levels, including environmental factors, metabolic determinants, ethnicity and a variety of other polymorphisms within the PAI-1 gene [35–38]. It remains unclear whether and to what extent these factors contribute to the variability in PAI-1 levels in dengue virus infected individuals. Previously studied individuals were either healthy, were patients with coronary artery disease, or were patients with diabetes mellitus. Clearly these study populations cannot be compared to patients suffering from a severe infectious disease that is characterised by an overwhelming inflammatory response.
Several potential limitations of the present study should be noted. The 1996–1997 cohort was characterized with a high mortality rate of 27%. Although the exact reason for this high mortality remains to be determined, it is likely that it results from a combination of factors. Our study was performed in a Tertiary Hospital that serves a large part of Middle-Java. Patients may travel long distances to be treated in this hospital and it could well be that they are presented late in the course of disease. Initial fluid resuscitation according to WHO guidelines is generally insufficient in these cases and patients usually end up in profound shock. Despite admission at the Pediatric Intensive Care Unit mortality rate is high. In addition, the 1996–1997 rainy season was characterised by high numbers of patients admitted to hospitals because of DHF/DSS and high number of non-survivors. It is believed that an unusually virulent virus circulated that year although microbiological sampling could not be performed at that time because of limited resources.
Study size is an important issue in the establishment of an association between the insertion/deletion (4G/5G) polymorphism in the PAI-1 gene and clinical outcome. Hermans and colleagues previously found an association between the homozygous 4G deletion polymorphism and mortality from Neisseria meningitides infection among 129 patients from two different cohort groups . This association was also observed when the largest of the two cohort groups was studied separately, but was not seen in the smallest group in which only 37 patients were included. In order to obtain a sufficient number of patients, we therefore decided to combine the results of two different projects. This decision was based on the fact that these two projects included patients with the same ethnic background, used similar trial procedures and applied uniform diagnostic and clinical management procedures. Although mortality rates between the 1996–1997 cohort and the 2001–2003 cohort differed considerably, one must realise that in the 1996–1997 cohort only DSS patients were included. In the 2001–2003 cohort also included patients who had no evidence of circulatory failure were included. Mortality rate among DSS patients included in the 2001–2003 cohort was 18%. Our findings of similar frequencies of the PAI-1 genotypes within the 1996–1997 project and the 2001–2003 project supports our decision to combine both groups.
In conclusion, this study demonstrates that high PAI-1 plasma levels are associated with an increased risk of death from dengue without the 4G/5G polymorphism in the promotor of the gene for PAI-1 playing a role. Additional studies are needed to explore the possibility of other polymorphisms within the PAI-1 gene and factors, like ethnicity or environmental factors, contributing to the variability of PAI-1 plasma concentrations in patients with dengue.
This project was supported by a grant from the Royal Netherlands Academy of Arts and Sciences.
H. ten Cate is a Clinical Established Investigator of the Netherlands Heart Foundation.
Besides the authors, the following investigators participated in this study: Indonesia: C. Suharti, R. Djokomoeljanto (Department of Internal Medicine, dr. Kariadi Hospital, University of Diponegoro, Semarang); A. Soemantri (Department of Paediatrics, dr. Kariadi Hospital, University of Diponegoro, Semarang); K. Djamiatun (Medical Faculty, University of Diponegoro, Semarang, Indonesia). The Netherlands: J.W.M. van der Meer, W.M.V. Dolmans (Department of Internal Medicine, University Medical Centre St. Radboud, Radboud University Nijmegen, Nijmegen); Y.T. van der Heide (Clinical Chemistry and Hematology Laboratory, Slotervaart Hospital, Amsterdam); K. Stittelaar (Institute of Virology, Erasmus Medical Centre, Rotterdam); E. Vogels (Laboratory for Experimental Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam); K. Joop (Hematology and Clinical Chemistry Laboratory, Onze Lieve Vrouwe Gasthuis, Amsterdam).
- Rigau-Perez JG, Clark GG, Gubler DJ, Reiter P, Sanders EJ, Vorndam AV: Dengue and dengue haemorrhagic fever. Lancet 1998, 352: 971-977. 10.1016/S0140-6736(97)12483-7View ArticlePubMed
- Dengue Haemorrhagic Fever: Diagnosis, treatment, prevention and control 2nd edition. World Health Organisation; 1997.
- Hales S, de Wet N, Maindonald J, Woodward A: Potential effect of population and climate changes on global distribution of dengue fever: an empirical model. Lancet 2002, 360: 830-834. 10.1016/S0140-6736(02)09964-6View ArticlePubMed
- Mairuhu AT, Mac Gillavry MR, Setiati TE, Soemantri A, ten Cate H, Brandjes DP, van Gorp EC: Is clinical outcome of dengue-virus infections influenced by coagulation and fibrinolysis? A critical review of the evidence. Lancet Infect Dis 2003, 3: 33-41. 10.1016/S1473-3099(03)00487-0View ArticlePubMed
- van Gorp EC, Minnema MC, Suharti C, Mairuhu AT, Brandjes DP, ten Cate H, Hack CE, Meijers JC: Activation of coagulation factor XI, without detectable contact activation in dengue haemorrhagic fever. Br J Haematol 2001, 113: 94-99. 10.1046/j.1365-2141.2001.02710.xView ArticlePubMed
- van Gorp EC, Setiati TE, Mairuhu AT, Suharti C, Cate HH, Dolmans WM, van der Meer JW, Hack CE, Brandjes DP: Impaired fibrinolysis in the pathogenesis of dengue hemorrhagic fever. J Med Virol 2002, 67: 549-554. 10.1002/jmv.10137View ArticlePubMed
- Wills BA, Oragui EE, Stephens AC, Daramola OA, Dung NM, Loan HT, Chau NV, Chambers M, Stepniewska K, Farrar JJ, Levin M: Coagulation Abnormalities in Dengue Hemorrhagic Fever: Serial Investigations in 167 Vietnamese Children with Dengue Shock Syndrome. Clin Infect Dis 2002, 35: 277-285. 10.1086/341410View ArticlePubMed
- Hermans PW, Hibberd ML, Booy R, Daramola O, Hazelzet JA, de Groot R, Levin M: 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet 1999, 354: 556-560. 10.1016/S0140-6736(99)02220-5View ArticlePubMed
- Westendorp RG, Hottenga JJ, Slagboom PE: Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 1999, 354: 561-563. 10.1016/S0140-6736(98)09376-3View ArticlePubMed
- de Boer JP, Abbink JJ, Brouwer MC, Meijer C, Roem D, Voorn GP, Lambers JW, van Mourik JA, Hack CE: PAI-1 synthesis in the human hepatoma cell line HepG2 is increased by cytokines--evidence that the liver contributes to acute phase behaviour of PAI-1. Thromb Haemost 1991, 65: 181-185.PubMed
- Mansfield MW, Stickland MH, Grant PJ: Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes. Thromb Haemost 1995, 74: 1032-1034.PubMed
- Groen J, Koraka P, Velzing J, Copra C, Osterhaus AD: Evaluation of six immunoassays for detection of dengue virus-specific immunoglobulin M and G antibodies. Clin Diagn Lab Immunol 2000, 7: 867-871. 10.1128/CDLI.7.6.867-871.2000PubMed CentralPubMed
- Koraka P, Burghoorn-Maas CP, Falconar A, Setiati TE, Djamiatun K, Groen J, Osterhaus AD: Detection of immune-complex-dissociated nonstructural-1 antigen in patients with acute dengue virus infections. J Clin Microbiol 2003, 41: 4154-4159. 10.1128/JCM.41.9.4154-4159.2003PubMed CentralView ArticlePubMed
- Passing H, Bablok W: Comparison of several regression procedures for method comparison studies and determination of sample sizes. Application of linear regression procedures for method comparison studies in Clinical Chemistry, Part II. J Clin Chem Clin Biochem 1984, 22: 431-445.PubMed
- Meijer P, Pollet DE, Wauters J, Kluft C: Specificity of antigen assays of plasminogen activator inhibitor in plasma: Innotest PAI-1 immunoassay evaluated. Clin Chem 1994, 40: 110-115.PubMed
- Brandtzaeg P, Joo GB, Brusletto B, Kierulf P: Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. Thromb Res 1990, 57: 271-278. 10.1016/0049-3848(90)90326-8View ArticlePubMed
- Kornelisse RF, Hazelzet JA, Savelkoul HF, Hop WC, Suur MH, Borsboom AN, Risseeuw-Appel IM, van V, de Groot R: The relationship between plasminogen activator inhibitor-1 and proinflammatory and counterinflammatory mediators in children with meningococcal septic shock. J Infect Dis 1996, 173: 1148-1156.View ArticlePubMed
- Mesters RM, Florke N, Ostermann H, Kienast J: Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis. Thromb Haemost 1996, 75: 902-907.PubMed
- Paramo JA, Perez JL, Serrano M, Rocha E: Types 1 and 2 plasminogen activator inhibitor and tumor necrosis factor alpha in patients with sepsis. Thromb Haemost 1990, 64: 3-6.PubMed
- Pralong G, Calandra T, Glauser MP, Schellekens J, Verhoef J, Bachmann F, Kruithof EK: Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 1989, 61: 459-462.PubMed
- Kruithof EK, Tran-Thang C, Ransijn A, Bachmann F: Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood 1984, 64: 907-913.PubMed
- Pannekoek H, Veerman H, Lambers H, Diergaarde P, Verweij CL, van Zonneveld AJ, van Mourik JA: Endothelial plasminogen activator inhibitor (PAI): a new member of the Serpin gene family. EMBO J 1986, 5: 2539-2544.PubMed CentralPubMed
- Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM: The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993, 268: 10739-10745.PubMed
- Ryan MP, Kutz SM, Higgins PJ: Complex regulation of plasminogen activator inhibitor type-1 (PAI-1) gene expression by serum and substrate adhesion. Biochem J 1996, 314 ( Pt 3): 1041-1046.View Article
- Bethell DB, Flobbe K, Cao XT, Day NP, Pham TP, Buurman WA, Cardosa MJ, White NJ, Kwiatkowski D: Pathophysiologic and prognostic role of cytokines in dengue hemorrhagic fever. J Infect Dis 1998, 177: 778-782.View ArticlePubMed
- Green S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Suntayakorn S, Nisalak A, Lew R, Innis BL, Kurane I, Rothman AL, Ennis FA: Early immune activation in acute dengue illness is related to development of plasma leakage and disease severity. J Infect Dis 1999, 179: 755-762. 10.1086/314680View ArticlePubMed
- Nguyen TH, Lei HY, Nguyen TL, Lin YS, Huang KJ, Le BL, Lin CF, Yeh TM, Do QH, Vu TQ, Chen LC, Huang JH, Lam TM, Liu CC, Halstead SB: Dengue hemorrhagic fever in infants: a study of clinical and cytokine profiles. J Infect Dis 2004, 189: 221-232. 10.1086/380762View ArticlePubMed
- Eriksson P, Kallin B, 't Hooft FM, Bavenholm P, Hamsten A: Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 1995, 92: 1851-1855.PubMed CentralView ArticlePubMed
- Wing LR, Hawksworth GM, Bennett B, Booth NA: Clearance of t-PA, PAI-1, and t-PA-PAI-1 complex in an isolated perfused rat liver system. J Lab Clin Med 1991, 117: 109-114.PubMed
- Hayashi T, Kamogawa A, Ro S, Yamaguchi K, Kobayashi Y, Takahashi Y, Murayama M: Plasma from patients with cirrhosis increases tissue plasminogen activator release from vascular endothelial cells in vitro. Liver 1998, 18: 186-190.View ArticlePubMed
- Tran-Thang C, Fasel-Felley J, Pralong G, Hofstetter JR, Bachmann F, Kruithof EK: Plasminogen activators and plasminogen activator inhibitors in liver deficiencies caused by chronic alcoholism or infectious hepatitis. Thromb Haemost 1989, 62: 651-653.PubMed
- Mohan B, Patwari AK, Anand VK: Hepatic dysfunction in childhood dengue infection. J Trop Pediatr 2000, 46: 40-43. 10.1093/tropej/46.1.40View ArticlePubMed
- Pancharoen C, Rungsarannont A, Thisyakorn U: Hepatic dysfunction in dengue patients with various severity. J Med Assoc Thai 2002, 85 Suppl 1: S298-S301.PubMed
- Souza LJ, Alves JG, Nogueira RM, Gicovate NC, Bastos DA, Siqueira EW, Souto Filho JT, Cezario TA, Soares CE, Carneiro RC: Aminotransferase changes and acute hepatitis in patients with dengue fever: analysis of 1,585 cases. Braz J Infect Dis 2004, 8: 156-163.View ArticlePubMed
- Festa A, D'Agostino RJ, Rich SS, Jenny NS, Tracy RP, Haffner SM: Promoter (4G/5G) plasminogen activator inhibitor-1 genotype and plasminogen activator inhibitor-1 levels in blacks, Hispanics, and non-Hispanic whites: the Insulin Resistance Atherosclerosis Study. Circulation 2003, 107: 2422-2427. 10.1161/01.CIR.0000066908.82782.3AView ArticlePubMed
- Henry M, Chomiki N, Scarabin PY, Alessi MC, Peiretti F, Arveiler D, Ferrieres J, Evans A, Amouyel P, Poirier O, Cambien F, Juhan-Vague I: Five frequent polymorphisms of the PAI-1 gene: lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population. Arterioscler Thromb Vasc Biol 1997, 17: 851-858.View ArticlePubMed
- Henry M, Tregouet DA, Alessi MC, Aillaud MF, Visvikis S, Siest G, Tiret L, Juhan-Vague I: Metabolic determinants are much more important than genetic polymorphisms in determining the PAI-1 activity and antigen plasma concentrations: a family study with part of the Stanislas Cohort. Arterioscler Thromb Vasc Biol 1998, 18: 84-91.View ArticlePubMed
- Mansfield MW, Stickland MH, Grant PJ: Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost 1995, 74: 842-847.PubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.