The features of secretory activity of platelets and fibrinolysis in women with various types of hypertensive disorders in the third trimester of pregnancy

Введение. Гипертензивные расстройства при беременности характеризуются нарушением адаптационных механизмов в системе свертывания крови и фибринолиза, важными участниками которой являются тромбоциты и эндотелий. Выраженность нарушений в тромбоцитарном звене гемостаза и системе фибринолиза при гипертензивных расстройствах при беременности различна. Цель исследования: изучить особенности секреторной активности тромбоцитов и компонентов фибринолитической системы у женщин с гипертензивными расстройствами различного генеза в III триместре беременности. Материалы и методы. Обследовано 238 женщин в III триместре беременности: 70 нормотензивных женщин, 32 — с умеренной преэклампсией (ПЭ), 47 — с тяжелой ПЭ, 58 — с хронической артериальной гипертензией (АГ) и 30 — с ПЭ на фоне хронической АГ. Проведен анализ количества и средней концентрации компонентов тромбоцитов, индуцированной секреции тромбоцитами АТФ, уровня бета-тромбоглобулина и тромбоцитарного фактора 4 в плазме крови. Фибринолитическую систему оценивали путем определения уровня лизиса сгустка, концентраций тканевого активатора плазминогена (t- PA) и ингибитора активатора плазминогена 1-го типа (PAI-1) в плазме крови. Результаты. Полученные данные свидетельствуют о различной степени выраженности нарушений в системе гемостаза при гипертензивных расстройствах различного генеза. При умеренной и тяжелой ПЭ выявлено повышение уровней t- PA и PAI-1, дополнительно при тяжелой ПЭ установлено снижение количества тромбоцитов и секреции активированными тромбоцитами АТФ на фоне повышения их гранулоцитарности. При ПЭ на фоне хронической АГ определено снижение секреции активированными тромбоцитами АТФ на фоне повышения их гранулоцитарности и базальной секреции β-тромбоглобулина и увеличение содержания в плазме крови t- PA и PAI-1. При хронической АГ обнаружено повышение количества тромбоцитов. Заключение. Выявлен- ные изменения позволили сделать вывод о неоднородности изменений в системе гемостаза у беременных с различными формами гипертензивных расстройств в III триместре беременности. Background. Hypertensive disturbances during pregnancy are jointly with the adaptive disorders of both blood coagulation and fibrinolysis, and platelets and endothelium plays important role for that. The disorders severity of platelet hemostasis and fibrinolysis is various in pregnant women with hypertensive disturbances. Objectives: to study the platelets secretory activity and some fibrinolytic components in women with hypertensive disturbances of various genesis in the III trimester of pregnancy. Patients / Methods. We examined 238 women in the III trimester of pregnancy: 70 normotensive women, 32 with moderate preeclampsia (PE), 47 with severe PE, 58 with chronic arterial hypertension (AH), and 30 with PE joint with chronic AH. The lab testing included the number and average concentration of platelet components, platelet-induced secretion of ATP, the β-thromboglobulin and platelet factor 4 in blood plasma. Fibrinolytic system was tested with determining of clot lysis level, tissue plasminogen activator (t- PA) and plasminogen activator inhibitor type 1 (PAI-1) in plasma. Results. Obtained data showed different severity of hemostasis disturbances in hypertensive disturbances of various genesis. In moderate and severe PE increased levels of t- PA and PAI-1 were revealed; in addition, in severe PE, decreased platelets number and ATP secretion by activated platelets was detected with increasing of their granulocyticity. In PE with chronic AH, decreased ATP secretion by activated platelets with increasing of their granulocyticity and basal secretion of beta-thromboglobulin was found, also increased t- PA and PAI-1 plasma content was determined. Increased platelet count was detected in chronic AH. Conclusions. Revealed changes led to the conclusion about the heterogeneity of hemostasis changes in pregnant women with various forms of hypertensive disturbances in the III trimester of pregnancy.

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Reduction in Factor VII, Fibrinogen and Plasminogen Activator Inhibitor-1 Activity after Surgical Treatment of Morbid Obesity

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646284 ◽

1992 ◽

Vol 68 (04) ◽

pp. 396-399 ◽

Cited By ~ 70

Author(s):

J N Primrose ◽

J A Davies ◽

C R M Prentice ◽

R Hughes ◽

D Johnston

Keyword(s):

Morbid Obesity ◽

Surgical Treatment ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Factor Vii ◽

Clot Lysis ◽

Plasminogen Activator Inhibitor 1 ◽

Platelet Factor ◽

Activator Inhibitor ◽

Pai 1

SummaryThe aim of this study was to determine the effects of the surgical treatment of morbid obesity on some aspects of haemostatic and fibrinolytic function. Measurement of haemostatic and fibrinolytic factors was performed before and again 6 and 12 months after operation in 19 patients suffering from morbid obesity. Surgical treatment resulted in a mean decrease in body weight of 50 kg at 6 months and 64 kg at 12 months. Weight loss was accompanied at 12 months by significant reductions in median (interquartile range) concentrations of serum cholesterol from 5.3 (4.5–6.2) mmol/1 to 3.6 (2.9–4.6) mmol/1; factor VII from 113 (92–145)% of normal to 99 (85–107)%; of fibrinogen from 3.5 (3–9.3) g/1 to 2.8 (2.4–3.8) g/1; and of plasminogen activator inhibitor-1 (PAI-1) activity from 21 (11–30) IU/ml to 6.3 (5–10) IU/ml. The decrease in PAI-1 activity probably accounted for a significant reduction in euglobulin clot lysis time. Tissue plasminogen activator activity was undetectable in most patients pre-operatively but increased slightly after 1 year to 110 (100–204) mIU/ml. There were no significant changes in plasma levels of KCCT, factor VIII, von Willebrand factor antigen, alpha-2-antiplasmin, antithrombin III, protein C antigen, beta thromboglobulin, platelet factor 4, fibrinopeptide A or platelet count. These findings provide support for the hypothesis that the surgical treatment of morbid obesity may have a long-term beneficial effect on mortality from cardiovascular and thromboembolic disease.

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Activated Protein C Increases Fibrin Clot Lysis by Neutralization of Plasminogen Activator Inhibitor No Evidence for a Cofactor Role of Protein S

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647055 ◽

1988 ◽

Vol 60 (02) ◽

pp. 328-333 ◽

Cited By ~ 44

Author(s):

N J de Fouw ◽

Y F de Jong ◽

F Haverkate ◽

R M Bertina

Keyword(s):

Plasminogen Activator ◽

Protein C ◽

Blood Platelets ◽

Plasminogen Activator Inhibitor ◽

Protein S ◽

Tissue Type ◽

Clot Lysis ◽

Activator Inhibitor ◽

Pai 1

summaryThe effect of purified human activated protein G (APC) on fibrinolysis was studied using a clot iysis system consisting of purified glu-plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor (released from endothelial cells or blood platelets), fibrinogen, 125T-fibrinogen and thrombin. All proteins were of human origin.In this system APC could increase fibrinolysis in a dose dependent way, without affecting fibrin formation or fibrin crosslinking. However, this profibrinolytic effect of APC could only be observed when plasminogen activator inhibitor (PAI-l) was present. The effect of APC was completely quenched by pretreatment of APC with anti-protein C IgG or di-isopropylfluorophosphate. Addition of the cofactors of APC:protein S, Ca2+-ions and phospholipid-alone or in combination did not enhance the profibrinolytic effect of APC. These observations indicate that human APC can accelerate in vitro clot lysis by the inactivation of PAI-1 activity. However, the neutralization of PAI-1 by APC is independent of the presence or absence of protein S, phospholipid and Ca2+-ions.

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The Roles of α2-Antiplasmin and Plasminogen Activator Inhibitor 1 (PAI-1) in the Inhibition of Clot Lysis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649570 ◽

1993 ◽

Vol 70 (02) ◽

pp. 301-306 ◽

Cited By ~ 51

Author(s):

Linda A Robbie ◽

Nuala A Booth ◽

Alison M Croll ◽

Bruce Bennett

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Fibrin Clot ◽

Clot Lysis ◽

Plasminogen Activator Inhibitor 1 ◽

Dependent Inhibition ◽

Activator Inhibitor ◽

Pai 1

SummaryThe relative importance of the two major inhibitors of fibrinolysis, α2-antiplasmin (α2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified α2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to α2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 × 108/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, α2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of α2-AP, in such situations.

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Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients

Scientific Reports ◽

10.1038/s41598-020-80010-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yu Zuo ◽

Mark Warnock ◽

Alyssa Harbaugh ◽

Srilakshmi Yalavarthi ◽

Kelsey Gockman ◽

...

Keyword(s):

Plasminogen Activator ◽

Ex Vivo ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Bleeding Complications ◽

Clot Lysis ◽

Thrombosis Prophylaxis ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor ◽

Pai 1

AbstractPatients with coronavirus disease-19 (COVID-19) are at high risk for thrombotic arterial and venous occlusions. However, bleeding complications have also been observed in some patients. Understanding the balance between coagulation and fibrinolysis will help inform optimal approaches to thrombosis prophylaxis and potential utility of fibrinolytic-targeted therapies. 118 hospitalized COVID-19 patients and 30 healthy controls were included in the study. We measured plasma antigen levels of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) and performed spontaneous clot-lysis assays. We found markedly elevated tPA and PAI-1 levels in patients hospitalized with COVID-19. Both factors demonstrated strong correlations with neutrophil counts and markers of neutrophil activation. High levels of tPA and PAI-1 were associated with worse respiratory status. High levels of tPA, in particular, were strongly correlated with mortality and a significant enhancement in spontaneous ex vivo clot-lysis. While both tPA and PAI-1 are elevated among COVID-19 patients, extremely high levels of tPA enhance spontaneous fibrinolysis and are significantly associated with mortality in some patients. These data indicate that fibrinolytic homeostasis in COVID-19 is complex with a subset of patients expressing a balance of factors that may favor fibrinolysis. Further study of tPA as a biomarker is warranted.

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The interaction of plasminogen activator inhibitor 1 with plasminogen activators (tissue-type and urokinase-type) and fibrin: localization of interaction sites and physiologic relevance

Blood ◽

10.1182/blood.v78.2.401.401 ◽

1991 ◽

Vol 78 (2) ◽

pp. 401-409 ◽

Cited By ~ 78

Author(s):

J Keijer ◽

M Linders ◽

AJ van Zonneveld ◽

HJ Ehrlich ◽

JP de Boer ◽

...

Keyword(s):

Plasminogen Activator ◽

Regulatory Protein ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activators ◽

Tissue Type ◽

Clot Lysis ◽

Plasminogen Activator Inhibitor 1 ◽

Interaction Sites ◽

Activator Inhibitor ◽

Pai 1

Abstract Plasminogen activator inhibitor 1 (PAI-1), an essential regulatory protein of the fibrinolytic system, harbors interaction sites for plasminogen activators (tissue-type [t-PA] and urokinase-type [u-PA]) and for fibrin. In this study, anti-PAI-1 monoclonal antibodies (MoAbs) were used to identify interaction sites of PAI-1 with these components. The binding sites of 18 different MoAbs were established and are located on five distinct “linear” areas of PAI-1. MoAbs, binding to two distinct areas of PAI-1, are able to prevent the inhibition of t-PA by PAI-1. In addition, two interaction sites for fibrin were identified on PAI-1. The area located between amino acids 110 and 145 of PAI-1 contains a binding site for both components and its significance is discussed in the context of the t-PA inhibition by fibrin-bound PAI-1. Subsequently, the MoAbs were used to assess the role of platelet-PAI-1 in clot-lysis. An in vitro clot-lysis system was used to demonstrate that clot-lysis resistance is dependent on the presence of activated platelets and that PAI-1 is a major determinant for lysis-resistance. We propose that, upon activation of platelets, PAI-1 is fixed within the clot by binding to fibrin and retains its full capacity to inhibit t-PA and u-PA.

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Sex Differences in the Determinants of Fibrinolytic Activity

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614950 ◽

1998 ◽

Vol 79 (03) ◽

pp. 587-590 ◽

Cited By ~ 12

Author(s):

J. A. Cooper ◽

D. J. Howarth ◽

T. W. Meade ◽

G. J. Miller ◽

P. K. MacCallum

Keyword(s):

Plasminogen Activator ◽

Whole Blood ◽

Fibrinolytic Activity ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Clot Lysis ◽

Significant Difference ◽

Main Determinants ◽

Activator Inhibitor Type ◽

Pai 1

SummaryImpaired whole blood fibrinolytic activity (FA), measured by the dilute clot lysis time (DCLT), is associated with first episodes of ischaemic heart disease (IHD) in the Northwick Park Heart Study in men, especially under 55 years, and in women. In a community-based study to investigate possible determinants of the DCLT, and therefore to assess which fibrinolytic components might be predictors of first IHD events, we measured fibrinolytic variables in a sub-sample of 150 healthy adults (73 males, 77 females) randomly selected from a single general practice.Most of the variance in DCLT (68% in men, 63% in women) was explained by tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) activities. In multiple regression analysis there was a significant difference in the strength of the association of t-PA activity with DCLT in men compared to women (test for interaction p = 0.05), the association of t-PA activity with DCLT being significant in males but not in females. Plasma PAI-1 activity was strongly associated with DCLT in both sexes. There was no independent association of DCLT with plasma fibrinogen, t-PA antigen, other fibrinolytic inhibitors, body mass index, serum lipids or C-reactive protein.Plasma PAI-1 activity in females and both t-PA and PAI-1 activities in males are the main determinants of whole blood FA measured by DCLT. It is therefore likely that these modulators of the plasma fibrinolytic system are associated with the onset of first clinical episodes of IHD. Elevated levels of t-PA antigen were positively associated with DCLT after adjustment for age and sex and therefore indicate impaired rather than enhanced FA. Further studies of the association of FA with risk of IHD should include not only “global” measures but also assessment of t-PA and PAI-1 activities, particularly as our results suggest that their associations with IHD may differ in men and women.

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Cell-Free mRNA Concentrations of Plasminogen Activator Inhibitor-1 and Tissue-Type Plasminogen Activator Are Increased in the Plasma of Pregnant Women with Preeclampsia

Clinical Chemistry ◽

10.1373/clinchem.2006.081372 ◽

2007 ◽

Vol 53 (3) ◽

pp. 399-404 ◽

Cited By ~ 42

Author(s):

Yuditiya Purwosunu ◽

Akihiko Sekizawa ◽

Keiko Koide ◽

Antonio Farina ◽

Noroyono Wibowo ◽

...

Keyword(s):

Pregnant Women ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Maternal Plasma ◽

Tissue Type ◽

Plasminogen Activator Inhibitor 1 ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Activator Inhibitor ◽

Pai 1

Abstract Background: Detection of placental mRNA in maternal plasma has been reported in high-risk pregnancies. We attempted to investigate the concentrations of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) mRNA in maternal plasma in preeclampsia. Methods: Peripheral blood samples were obtained from healthy pregnant women before and after delivery and also from women with or without preeclampsia. Plasma was isolated from these samples, and RNA was extracted. Plasma PAI-1 and tPA mRNA concentrations were then measured by use of reverse transcription PCR assays. The concentrations were converted into multiples of the median (MoM) of the controls adjusted for gestational age. Data were stratified and analyzed according to the clinical severity of preeclampsia and quantitative distribution of blood pressure and proteinuria. Results: The median (minimum–maximum) PAI-1 mRNA MoM values for women with preeclampsia and controls were 2.48 (0.82–8.53) and 1.00 (0.41–2.33), respectively, whereas the median (minimum–maximum) tPA mRNA MoM values were 3.33 (1.01–10.58) and 1.00 (0.95–1.20), respectively. The concentrations of both PAI-1 and tPA mRNA were significantly increased in cases of preeclampsia, compared with controls (P <0.0001). The MoM values of both mRNA species were directly correlated with the severity of preeclampsia and were greatest among a subgroup of hemolysis, increased liver enzymes, and low platelets pregnancies. Conclusion: Maternal plasma PAI-1 and tPA mRNAs are significantly increased in patients with preeclampsia and are positively correlated with the severity of preeclampsia.

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MEASUREMENT OF PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) IN PLASMA WITH AN ELISA BASED ON TWO MURINE MONOCLONAL ANTIBODIES

10.1055/s-0038-1644449 ◽

1987 ◽

Cited By ~ 1

Author(s):

P J Declerck ◽

M C Alessi ◽

M Verstreken ◽

E K O Kruithof ◽

I Juhan-Vague ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Pregnant Women ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

First Trimester ◽

Enzyme Linked Immunosorbent Assay ◽

Plasminogen Activator Inhibitor 1 ◽

Murine Monoclonal Antibodies ◽

Activator Inhibitor ◽

Pai 1

An enzyme-linked immunosorbent assay (ELISA) for quantitation of plasminogen activator inhibitor 1 (PAI-1) was developed, based on two murine monoclonal antibodies (MA-7D4B7 and MA-7F5), raised against purified PAI-1 from HT-1080 fibrosarcoma cells, which react with non-overlapping epitopes. MA-7D4B7 was coated on microtiter plates and bound PAI-1 antigen was quantitated with MA-7F5 conjugated with horseradish peroxidase.In normal plasma, collected on citrate at pH 7.4, the PAI-1 level is 27 ± 16 ng/ml (mean ± SD, n=ll), with a corresponding value of 19 ± 11 ng/ml (n=12) in plasma collected on acid citrate pH 4.5, which inhibits the release of PAI-1 from platelets. The lower limit of the assay in plasma is 2 ng/ml; the intra-assay, inter-assay and inter-dilution coefficients of variation are 5.2%, 8.0% and 7.1% respectively.This ELISA was used to measure PAI-1 levels in plasma (collected on citrate, pH 7.4) of non-pregnant women and of women at different stages of pregnancy. A progressive increase is observed : before: 20±9 ng/ml, n=7; first trimester: 25 ± 12 ng/ml, n=5; second trimester: 40 ± 25 ng/ml, n=ll; third trimester: 98 ± 46 ng/ml, n=13. A correlation coefficient of 0.70 is found between the duration of pregnancy and the PAI-1 level.Preliminary data indicate that the PAI-1 antigen level is increased in several disease states, including myocardial infarction and deep vein thrombosis.Thus, this newly developed ELISA allows a direct measurement of the fast-acting inhibitor of plasminogen activator in plasma. Application of this assay to plasma of non-pregnant and pregnant women substantiates previous results obtained with the use of functional assays. In order to quantitate PAI-1 antigen circulating in plasma, blood should be collected under conditions that prevent platelet stimulation.

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Admission fibrinolytic profile predicts clot lysis resistance in stroke patients treated with tissue plasminogen activator

Thrombosis and Haemostasis ◽

10.1160/th04-02-0097 ◽

2004 ◽

Vol 91 (06) ◽

pp. 1146-1151 ◽

Cited By ~ 55

Author(s):

Joan Montaner ◽

Carlos Molina ◽

Juan Arenillas ◽

Esteban Santamarina ◽

José Alvarez-Sabín ◽

...

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Neurological Status ◽

Artery Occlusion ◽

Clot Lysis ◽

Term Outcome ◽

Long Term Outcome ◽

Fibrinolysis Inhibitor ◽

The Impact ◽

Pai 1

SummaryEndogenous fibrinolysis inhibitors may be involved in t-PA resistance, decreasing stroke thrombolysis beneficts. We aim to determine the impact of pretreatment levels of plasminogen activator inhibitor (PAI-1), lipoprotein(a), thrombin-activatable fibrinolysis inhibitor (TAFI) and homocysteine on arterial recanalization and outcome. Forty-four consecutive patients with acute proximal middle cerebral artery occlusion were studied, including assessment of transcraneal Doppler artery patency. The neurological status was determined by NIH Stroke Scale (NIHSS) and long-term outcome with modified Rankin Scale (mRS). Patients who recanalized after t-PA infusion had lower PAI-1 levels than those who remained occluded. Similarly, patients who achieved dramatic clinical recovery at 12 hours exhibited significantly lower PAI-1 levels as those independent (mRS≤2) at third month. We observed a trend towards lower lipoprotein p(a) in patients who achieved recanalization at 1 hour, whereas no relation was found between TAFI or homocysteine levels and recanalization. After a regression model was applied the only independent predictor of thrombolysis resistance was baseline PAI-1≤34 ng/ml, such that high PAI-1 levels interfere with tPA-induced recanalization in stroke, predicting a higher susceptibility towards clot-lysis resistance and poor outcome.

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Adenovirus-Mediated Transfer of Tissue-Type Plasminogen Activator Augments Thrombolysis in Tissue-Type Plasminogen Activator–Deficient and Plasminogen Activator Inhibitor-1–Overexpressing Mice

Blood ◽

10.1182/blood.v90.4.1527.1527_1527_1534 ◽

1997 ◽

Vol 90 (4) ◽

pp. 1527-1534

Author(s):

Peter Carmeliet ◽

Jean-Marie Stassen ◽

Ilse Van Vlaenderen ◽

Robert S. Meidell ◽

Désiré Collen ◽

...

Keyword(s):

Gene Transfer ◽

Plasminogen Activator ◽

Recombinant Adenovirus ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Clot Lysis ◽

Plasminogen Activator Inhibitor 1 ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Pai 1

Impaired fibrinolysis, resulting from increased plasminogen activator inhibitor-1 (PAI-1) or reduced tissue-type plasminogen activator (t-PA) plasma levels, may predispose the individual to subacute thrombosis in sepsis and inflammation. The objective of these studies was to show that adenovirus-mediated gene transfer could increase systemic plasma t-PA levels and thrombolytic capacity in animal model systems. Recombinant adenovirus vectors were constructed that express either human wild type or PAI-1–resistant t-PA from the cytomegalovirus (CMV) promoter. Both t-PA-deficient (t-PA−/−) and PAI-1–overexpressing transgenic mice were infected by intravenous injection of these viruses. Intravenous injection of recombinant adenovirus resulted in liver gene transfer, t-PA synthesis, and secretion into the plasma. Virus dose, human t-PA antigen, and activity concentrations in plasma and extent of lysis of a 125I-fibrin–labeled pulmonary embolism were all closely correlated. Plasma t-PA antigen and activity were increased approximately 1,000-fold above normal levels. Clot lysis was significantly increased in mice injected with a t-PA–expressing virus, but not in mice injected with saline or an irrelevant adenovirus. Comparable levels of enzyme activity and clot lysis were obtained with wild type and inhibitor-resistant t-PA viruses. Adenovirus-mediated t-PA gene transfer was found to augment clot lysis as early as 4 hours after infection, but expression levels subsided within 7 days. Adenovirus-mediated transfer of a t-PA gene can effectively increase plasma fibrinolytic activity and either restore (in t-PA–deficient mice) or augment (in PAI-1–overexpressing mice) the thrombolytic capacity in simple animal models of defective fibrinolysis.

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