Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding

Abstract A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is characterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(ogen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor XIII deficiency, alpha 2-antiplasmin deficiency, or dysfibrinogenemia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half normal antigen and normal activity of platelet PAI-1. The low concentration of plasma PAI-1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAI-1 deficiency. Studies on this patient emphasize a clear correlation between decreased plasma PAI-1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAI-1 in the balance between the coagulation and fibrinolytic mechanisms.

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Clonal studies of CD3- lymphoproliferative disease of granular lymphocytes

Blood ◽

10.1182/blood.v81.9.2363.bloodjournal8192363 ◽

1993 ◽

Vol 81 (9) ◽

pp. 2363-2368 ◽

Cited By ~ 1

Author(s):

R Nash ◽

P McSweeney ◽

R Zambello ◽

G Semenzato ◽

TP Jr Loughran

Keyword(s):

Coagulation Factor ◽

Normal Activity ◽

Lymphoproliferative Disease ◽

Clear Correlation ◽

Unique Role ◽

Delayed Bleeding ◽

History Of ◽

Granular Lymphocytes ◽

Pai 1

A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is characterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(ogen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor XIII deficiency, alpha 2-antiplasmin deficiency, or dysfibrinogenemia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half normal antigen and normal activity of platelet PAI-1. The low concentration of plasma PAI-1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAI-1 deficiency. Studies on this patient emphasize a clear correlation between decreased plasma PAI-1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAI-1 in the balance between the coagulation and fibrinolytic mechanisms

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Clonal studies of CD3- lymphoproliferative disease of granular lymphocytes

Blood ◽

10.1182/blood.v81.9.2363.2363 ◽

1993 ◽

Vol 81 (9) ◽

pp. 2363-2368 ◽

Cited By ~ 50

Author(s):

R Nash ◽

P McSweeney ◽

R Zambello ◽

G Semenzato ◽

TP Jr Loughran

Keyword(s):

Coagulation Factor ◽

Normal Activity ◽

Lymphoproliferative Disease ◽

Clear Correlation ◽

Unique Role ◽

Delayed Bleeding ◽

History Of ◽

Granular Lymphocytes ◽

Pai 1

Abstract A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is characterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(ogen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor XIII deficiency, alpha 2-antiplasmin deficiency, or dysfibrinogenemia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half normal antigen and normal activity of platelet PAI-1. The low concentration of plasma PAI-1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAI-1 deficiency. Studies on this patient emphasize a clear correlation between decreased plasma PAI-1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAI-1 in the balance between the coagulation and fibrinolytic mechanisms

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Plasminogen Activator Inhibitor 1 4G/5G Polymorphism and Coagulation Factor XIII Val34Leu Polymorphism: Impaired Fibrinolysis and Early Pregnancy Loss

Clinical Chemistry ◽

10.1373/49.7.1081 ◽

2003 ◽

Vol 49 (7) ◽

pp. 1081-1086 ◽

Cited By ~ 74

Author(s):

Astrid Dossenbach-Glaninger ◽

Michael van Trotsenburg ◽

Martin Dossenbach ◽

Christian Oberkanins ◽

Anne Moritz ◽

...

Keyword(s):

Early Pregnancy ◽

Pregnancy Loss ◽

Coagulation Factor ◽

Plasminogen Activator Inhibitor ◽

Carrier Status ◽

Early Pregnancy Loss ◽

Plasminogen Activator Inhibitor 1 ◽

History Of ◽

Activator Inhibitor ◽

Pai 1

Abstract Background: A successful outcome of pregnancy depends on proper placental formation. In the very beginning of this process, trophoblast invasion and fibrin deposition into the wall of the decidual veins play an important part. Two polymorphisms, coagulation factor XIII (FXIII) Val34Leu and plasminogen activator inhibitor 1 (PAI-1) 4G/5G, interfere with fibrin cross-linking and regulation of fibrinolysis and may therefore contribute to early pregnancy loss. Methods: We enrolled 49 unrelated Caucasian women with a history of two consecutive or three to six nonconsecutive early pregnancy losses and 48 unrelated parous healthy controls without a history of pregnancy loss and evaluated them for the following genetic variants: the factor V Leiden and prothrombin G20210A gene mutations, the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms, and the PAI-1 4G/5G and FXIII Val34Leu polymorphisms. Results: For the isolated occurrence of PAI-1 4G/5G or FXIII Val34Leu, we found no statistically significant difference between cases and controls. For homozygosity of either or compound carrier status of both mutations, the overall relative risk for early pregnancy loss was significantly increased (odds ratio = 2.4; 95% confidence interval, 1.1–5.5; P = 0.032). We observed no statistically relevant association of any of the other tested mutations with early pregnancy loss. Conclusion: Homozygosity for PAI-1 4G or FXIII 34Leu polymorphisms as well as compound carrier status is associated with early pregnancy loss.

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Role of fibrinolytic parameters and plasminogen activator inhibitor 1 (PAI-1) promoter polymorphism on premature atherosclerosis in SLE patients

Lupus ◽

10.1177/0961203311404911 ◽

2011 ◽

Vol 20 (10) ◽

pp. 1063-1071 ◽

Cited By ~ 7

Author(s):

M Bicakcigil ◽

DA Tasan ◽

N Tasdelen ◽

N Mutlu ◽

S Yavuz

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Promoter Polymorphism ◽

Plasminogen Activator Inhibitor 1 ◽

Premature Atherosclerosis ◽

Fibrinolytic Parameters ◽

Activator Inhibitor ◽

Pai 1

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Emerging Role of Endothelial and Inflammatory Markers in Preeclampsia

Disease Markers ◽

10.1155/2009/658943 ◽

2009 ◽

Vol 26 (3) ◽

pp. 127-133 ◽

Cited By ~ 6

Author(s):

Menha Swellam ◽

Nervana Samy ◽

Susan Abdl Wahab ◽

Mohamed Saeed Ibrahim

Keyword(s):

Inflammatory Markers ◽

Linear Regression Analysis ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

New Approach ◽

Reactive Protein ◽

Diagnostic Role ◽

Activator Inhibitor ◽

Pai 1

Objectives:Endothelial disturbance and excess inflammatory response are pathogenic mechanisms in pre-eclampsia (PE). Authors determine the clinical diagnostic role for thrombomodulin (TM), plasminogen activator inhibitor-1 (PAI-1) as endothelial markers and C-reactive protein (CRP), and interlukin-6 (IL-6) as inflammatory markers when tested independently or in combinations.Materials and methods:We conducted a retrospective study in a cohort of 185 women grouped as 80 women with PE, 55 normotensive pregnant and 50 healthy non-pregnant. Plasma levels of TM, PAI-1, CRP and IL-6 were examined using enzyme linked immunosorbent assays.Results:Median levels and the positivity rates for the investigated markers were higher in PE as compared to the other groups (P< 0.0001). Using linear regression analysis, the investigated markers were significantly correlated regarding healthy nonpregnantvsPE or normotensive pregnantvsPE. The sensitivity of PAI-1 was the highest (98%) among the tested biomarkers. Combination between the investigated markers revealed absolute sensitivity (100%) and reliable specificity especially when PAI-1 was combined with CRP at 83% specificity.Conclusions:Investigated endothelial and inflammatory markers revealed sensitive diagnostic test for PE. However, coupled combination between PAI-1 with CRP showed superior both sensitivity and specificity which represent a promising new approach for detection of PE.

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Role of plasminogen activator inhibitor-1 gene polymorphisms in osteoporosis: A study in Chinese post-menopausal women

European Journal of Inflammation ◽

10.1177/2058739218767292 ◽

2018 ◽

Vol 16 ◽

pp. 205873921876729

Author(s):

An Wan ◽

Daodong Liu

Keyword(s):

Gene Polymorphisms ◽

Chinese Women ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Chain Reaction ◽

Polymerase Chain ◽

Post Menopausal ◽

Activator Inhibitor ◽

Pai 1

Osteoporosis is a chronic multifactorial disease characterized by deterioration of bone mass and is vulnerable to bone fracture. Plasminogen activator inhibitor-1 (PAI-1) is an important molecule for maintenance of optimum bone mass. Several single-nucleotide polymorphisms (SNPs) in PAI-1 have been reported to alter PAI-1 expression and/or the translational level. In this report, we explored the possible role of common PAI-1 gene polymorphisms on predisposition to osteoporosis in a Chinese cohort. A total of 364 post-menopausal Chinese women diagnosed of having osteoporosis and 350 healthy females hailing from similar areas were enrolled in this study. Five common SNPs (−844G > A, −6754G/5G, +43G > A, +9785G > A and +11053T > G) were genotyped by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). Relative expression of PAI-1 mRNA and plasma PAI-1 levels were quantified by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Prevalence of homozygous mutant (5G/5G) and minor allele (5G) of PAI-1 (−675 4G/5G) polymorphism was significantly more frequent in patients than in healthy controls (5G/5G: P < 0.0001, odds ratio (OR) = 3.18; 5G: P < 0.0001, OR = 1.65). Both plasma PAI-1 and relative mRNA expression levels were significantly lower in patients compared to healthy controls. Interestingly, the quantity of plasma PAI-1 and mRNA expression was correlated with PAI-1 (−675 4G/5G) polymorphism: subjects with 4G/4G genotype had elevated PAI-1 in comparison to homozygous mutant, and displayed lower quantity of PAI-1 protein and mRNA values. PAI-1 (−675 4G/5G) mutant is associated with susceptibility to development of osteoporosis in post-menopausal Chinese women. Furthermore, this variant in the promoter region alters plasma protein levels and relative expression of PAI-1.

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Reactive oxygen species modulate HIF-1 mediated PAI-1 expression: involvement of the GTPase Rac1

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613480 ◽

2003 ◽

Vol 89 (05) ◽

pp. 926-935 ◽

Cited By ~ 50

Author(s):

Utta Berchner-Pfannschmidt ◽

Christoph Wotzlaw ◽

Robbert Cool ◽

Joachim Fandrey ◽

Helmut Acker ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Plasminogen Activator Inhibitor ◽

Dominant Negative ◽

Mrna Levels ◽

Ros Production ◽

Oxygen Species ◽

Plasminogen Activator Inhibitor 1 ◽

Pai 1

SummaryThe hypoxia-inducible transcription factor HIF-1 mediates upregulation of plasminogen activator inhibitor-1 (PAI-1) expression under hypoxia. Reactive oxygen species (ROS) have also been implicated in PAI-1 gene expression. However, the role of ROS in HIF-1-mediated regulation of PAI-1 is not clear. We therefore investigated the role of the GTPase Rac1 which modulates ROS production in the pathway leading to HIF-1 and PAI-1 induction.Overexpression of constitutively activated (RacG12V) or dominant-negative (RacT17N) Rac1 increased or decreased, respectively, ROS production. In RacG12V-expressing cells, PAI-1 mRNA levels as well as HIF-1α nuclear presence were reduced under normoxia and hypoxia whereas expression of RacT17N resulted in opposite effects. Treatment with the antioxidant pyrrolidinedithiocarbamate or coexpression of the redox factor-1 restored HIF-1 and PAI-1 promoter activity in RacG12V-cells. In contrast, NFκB activation was enhanced in RacG12V-cells, but abolished by RacT17N. Thus, these findings suggest a mechanism explaining modified fibrinolysis and tissue remodeling in an oxidized environment.

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Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay

Blood ◽

10.1182/blood.v71.1.220.bloodjournal711220 ◽

1988 ◽

Vol 71 (1) ◽

pp. 220-225 ◽

Cited By ~ 325

Author(s):

PJ Declerck ◽

MC Alessi ◽

M Verstreken ◽

EK Kruithof ◽

I Juhan-Vague ◽

...

Keyword(s):

Plasminogen Activator ◽

Immunosorbent Assay ◽

Healthy Subjects ◽

Plasminogen Activator Inhibitor ◽

Enzyme Linked Immunosorbent Assay ◽

Plasminogen Activator Inhibitor 1 ◽

Platelet Poor Plasma ◽

Activator Inhibitor ◽

Pai 1

An enzyme-linked immunosorbent assay for plasminogen activator inhibitor-1 (PAI-1) in biologic fluids was developed on the basis of two murine monoclonal antibodies raised against PAI-1 purified from HT- 1080 fibrosarcoma cells. The lower limit of sensitivity of the assay in plasma is 2 ng/mL. The assay is 12 times less sensitive toward the PAI- 1/human tissue-type plasminogen activator (t-PA) complex as compared with free PAI-1. The intraassay, interassay, and interdilution coefficients of variation are 5.2%, 8.0%, and 7.1%, respectively. The level of PAI-1 in platelet-poor plasma of healthy subjects is 18 +/- 10 ng/mL (mean +/- SD, n = 45). In platelet-rich plasma after freezing and thawing, 92% of PAI-1 antigen is released from platelets, whereas only 8% is found in the corresponding platelet-poor plasma. In platelet-poor plasma from healthy subjects, a linear correlation (r = 0.80) was found between PAI activity and PAI-1 antigen. In plasma approximately two thirds of the PAI-1 antigen was functionally active, whereas only 5% of the PAI-1 antigen released from platelets was active. During pregnancy a progressive increase of PAI-1 antigen levels up to three- to sixfold the control value was observed. In plasma of patients with recurrent deep vein thrombosis, PAI-1 levels were 44 +/- 20 ng/mL (mean +/- SD, n = 7), during a clinically silent phase. Four of these patients had a level above 38 ng/mL (mean +/- 2 SD of normal). The present assay, based on stable and reproducible reagents, allows the specific determination of PAI-1 antigen in biologic fluids. It may facilitate interlaboratory comparisons and be useful for further investigations of the role of PAI-1 in clinical conditions associated with impaired fibrinolysis and/or a tendency to thrombosis and investigations of the role of PAI-1 in platelets.

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Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay

Blood ◽

10.1182/blood.v71.1.220.220 ◽

1988 ◽

Vol 71 (1) ◽

pp. 220-225 ◽

Cited By ~ 72

Author(s):

PJ Declerck ◽

MC Alessi ◽

M Verstreken ◽

EK Kruithof ◽

I Juhan-Vague ◽

...

Keyword(s):

Plasminogen Activator ◽

Immunosorbent Assay ◽

Healthy Subjects ◽

Plasminogen Activator Inhibitor ◽

Enzyme Linked Immunosorbent Assay ◽

Plasminogen Activator Inhibitor 1 ◽

Platelet Poor Plasma ◽

Activator Inhibitor ◽

Pai 1

Abstract An enzyme-linked immunosorbent assay for plasminogen activator inhibitor-1 (PAI-1) in biologic fluids was developed on the basis of two murine monoclonal antibodies raised against PAI-1 purified from HT- 1080 fibrosarcoma cells. The lower limit of sensitivity of the assay in plasma is 2 ng/mL. The assay is 12 times less sensitive toward the PAI- 1/human tissue-type plasminogen activator (t-PA) complex as compared with free PAI-1. The intraassay, interassay, and interdilution coefficients of variation are 5.2%, 8.0%, and 7.1%, respectively. The level of PAI-1 in platelet-poor plasma of healthy subjects is 18 +/- 10 ng/mL (mean +/- SD, n = 45). In platelet-rich plasma after freezing and thawing, 92% of PAI-1 antigen is released from platelets, whereas only 8% is found in the corresponding platelet-poor plasma. In platelet-poor plasma from healthy subjects, a linear correlation (r = 0.80) was found between PAI activity and PAI-1 antigen. In plasma approximately two thirds of the PAI-1 antigen was functionally active, whereas only 5% of the PAI-1 antigen released from platelets was active. During pregnancy a progressive increase of PAI-1 antigen levels up to three- to sixfold the control value was observed. In plasma of patients with recurrent deep vein thrombosis, PAI-1 levels were 44 +/- 20 ng/mL (mean +/- SD, n = 7), during a clinically silent phase. Four of these patients had a level above 38 ng/mL (mean +/- 2 SD of normal). The present assay, based on stable and reproducible reagents, allows the specific determination of PAI-1 antigen in biologic fluids. It may facilitate interlaboratory comparisons and be useful for further investigations of the role of PAI-1 in clinical conditions associated with impaired fibrinolysis and/or a tendency to thrombosis and investigations of the role of PAI-1 in platelets.

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