Abstract:
:Plasminogen activator inhibitor 1 (PAI-1) is the main inhibitor of tissue-type and urokinase-type plasminogen activators (t/uPA) and plays an important role in fibrinolysis. Inhibition of PAI-1 activity prevents thrombosis and accelerates fibrinolysis, indicating that PAI-1 inhibitors may be used as effective antithrombotic agents. We previously designed a PAI-1 inhibitor (PAItrap) which is a variant of inactivated urokinase protease domain. In the present study, we fused PAItrap with human serum albumin (HSA) to develop a long-acting PAI-1 inhibitor. Unfortunately, the fusion protein PAItrap-HSA lost some potency compared to PAItrap (33 nM vs 10 nM). Guided by computational method, we carried out further optimisation to enhance inhibitory potency for PAI-1. The new PAItrap, denominated PAItrap(H37R)-HSA, which was the H37R variant of PAItrap fused to HSA, gave a six-fold improvement of IC50 (5 nM) for human active PAI-1 compared to PAItrap-HSA, and showed much longer plasma half-life (200-fold) compared to PAItrap. We further demonstrated that the PAItrap(H37R)-HSA inhibited exogenous or endogenous PAI-1 to promote fibrinolysis in fibrin-clot lysis assay. PAItrap(H37R)-HSA inhibits murine PAI-1 with IC50 value of 12 nM, allowing the inhibitor to be evaluated in murine models. Using an intravital microscopy, we demonstrated that PAItrap(H37R)-HSA blocks thrombus formation and platelet accumulation in vivo in a laser-induced vascular injury mouse model. Additionally, mouse tail bleeding assay showed that PAItrap(H37R)-HSA did not affect the global haemostasis. These results suggest that PAItrap(H37R)-HSA have the potential benefit to prevent thrombosis and accelerates fibrinolysis.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Peng S,Xue G,Gong L,Fang C,Chen J,Yuan C,Chen Z,Yao L,Furie B,Huang Mdoi
10.1160/TH16-11-0891subject
Has Abstractpub_date
2017-06-28 00:00:00pages
1338-1347issue
7eissn
0340-6245issn
2567-689Xpii
16-11-0891journal_volume
117pub_type
杂志文章abstract::DX-9065a is an antithrombin III (AT III)-independent and selective inhibitor of activated blood coagulation factor X (FXa). We evaluated the effects of DX-9065a and warfarin on bleeding time and blood loss in rat tail transection model and on blood loss in hydrochloride (HCl)-induced rat gastrointestinal haemorrhage m...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1999-05-01 00:00:00
abstract::Thrombus formation at an artificial surface in contact with blood is a complex process that encompasses accretion of platelets from flowing blood and fibrin deposition. Platelet adhesion and fibrin formation are intimately intertwined reactions that are triggered by different sets of surface adsorbed plasma proteins. ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2002-04-01 00:00:00
abstract::Neuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the bl...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,评审
doi:10.1160/TH03-12-0766
更新日期:2004-03-01 00:00:00
abstract::D-dimer, a degradation product of fibrin, is being increasingly used as a marker and prognostic factor in various thrombotic diseases. Previous reports have shown that obstructive sleep apnea is associated with platelet activation and hypercoagulability. The aim of the study was to assess the potential role of the pla...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2005-09-01 00:00:00
abstract::ADP or thrombin caused a transient change in creatine phosphate (CP) content of rat platelets. At 25 degrees C the CP content decreased most 30 sec after the addition of ADP or thrombin and recovered thereafter. ATP or AMP was without effect. The rat platelets aggregated at 25 degrees C by ADP or thrombin, but the cha...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1979-08-31 00:00:00
abstract::Activation of coagulation was studied during the peri-operative period in patients undergoing cardiopulmonary bypass (CPB) surgery using activation markers which have recently become available: prothrombin fragment F1 + 2 (F1 + 2), which is a measure of total thrombin generation, and thrombin-antithrombin complex, whi...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1993-08-02 00:00:00
abstract::The behavior of direct fibrinolytic (non-plasmin) proteinase activity and plasminogen-activator activity in the lung and spleen was investigated in rats after a single intravenous injection of bacterial endotoxin, and the influence of thrombin inhibitors on the effects of the endotoxin was assessed. The non-plasmin fi...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1985-06-24 00:00:00
abstract::Congenital amegakaryocytic thrombocytopaenia (CAMT) is a disorder caused by c-MPL mutations that impair thrombopoietin (TPO) signalling, resulting in a near absence of megakaryocytes (MKs). While this phenotype is consistent in adults, neonates with CAMT can present with severe thrombocytopaenia despite normal MK numb...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH17-06-0433
更新日期:2017-12-01 00:00:00
abstract::Endotoxin (LPS) and interleukin-1 beta (IL-1 beta) increased in a dose-dependent manner the expression of tissue factor, an ubiquitous membrane-anchored glycoprotein that initiates blood coagulation at the surface of human umbilical vein endothelial cells (HUVEC and human peripheral blood mononuclear cells (PBMC). Ech...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1996-02-01 00:00:00
abstract::The administration of recombinant activated factor VII (rFVIIa) by continuous infusion has provided a safe and convenient alternative to bolus injections in haemophiliacs with inhibitors, but it has only been reported in a single case with congenital factor VII (FVII) deficiency. The results of 12 consecutive surgical...
journal_title:Thrombosis and haemostasis
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1160/TH05-05-0342
更新日期:2005-12-01 00:00:00
abstract::Inherited severe hypoplasminogenaemia is a multisystemic disorder leading to deficient extravascular fibrinolysis. As a clinical consequence wound healing capacity of mucous membranes is markedly impaired leading to ligneous conjunctivitis and several other manifestations. Here we report the molecular genetic and clin...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH10-04-0216
更新日期:2011-03-01 00:00:00
abstract::Several members of a family from Scranton, Pennsylvania were identified to have normal levels of prothrombin antigen while their prothrombin clotting activity was approximately 50% of normal. There has been no previous history of bleeding or other clinical manifestations in this family. The genomic DNA from the proban...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2001-04-01 00:00:00
abstract::Nuclear DNA-binding protein high mobility group box 1 (HMGB1) acts as a late mediator of severe vascular inflammatory conditions, such as sepsis. Activated factor X (FXa) is an important player in the coagulation cascade responsible for thrombin generation, and it influences cell signalling in various cell types by ac...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH14-03-0233
更新日期:2014-10-01 00:00:00
abstract::Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH16-09-0716
更新日期:2017-01-26 00:00:00
abstract::We have identified two novel minor deletions (case 1; -TA or -AT at nucleotide 9831-3 in exon 5 and case 2; -A at nucleotide 7640-1 in exon 4), one novel nonsense mutation (case 3; TAT to TAA at nucleotide 7491 in exon 4), and one recurrent nonsense mutation (case 4; CGA to TGA at nucleotide 5381 in exon 3A) in Japane...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1997-04-01 00:00:00
abstract::An assay of human antiplasmins has been developed utilizing radial diffusion of plasma from wells cut in plasmin-enriched, fibrinogen-agarose plates. After diffusion the fibrinogen is clotted. Zones of fibrin protected from background fibrinolysis develop as the result of plasma antiplasmin activity. A pooled plasma s...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1978-04-30 00:00:00
abstract::An assay system for protein C (PC) activity and PC-inhibitor in plasma was developed. The assay was based on: (1) binding of PC to wells of a microtiter plate coated with a murine monoclonal anti-PC antibody (C3) that did not interfere with the activity or activation of PC; (2) activation of immobilized PC with Protac...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1989-02-28 00:00:00
abstract::Heparin-associated thrombocytopenia (HAT) is a severe complication of heparin therapy. Its diagnosis is difficult. Conventional assays employ platelet aggregometry (PAA) and/or 14C-serotonin release (SRA) which are either insensitive (PAA) or require radioactive tracers (SRA). We here describe a newly developed sensit...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1991-12-02 00:00:00
abstract::We measured and compared the levels of plasma soluble (s) P-selectin, sCD40L, platelet-derived microparticles (PDMP), monocyte-derived microparticles (MDMP), and anti-oxidized LDL antibody, to obtain a better understanding of their potential contribution to vascular complications in acute coronary syndrome (ACS). The ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH03-04-0247
更新日期:2004-01-01 00:00:00
abstract::Bleeding time and platelet function tests were performed on 31 patients with progressive chronic renal failure (CRF) due to non-immunological (urological) causes, and compared with 22 healthy controls. Patients were classified as mild (plasma creatinine less than 300 mumol/l), moderate (300-600 mumol/l) or severe rena...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1988-08-30 00:00:00
abstract::It was the objective of this study to determine whether reduced cleavage of von Willebrand factor (VWF) multimers following aortic valve replacement (AVR) is a consequence of reduced shear stress or postoperative changes in VWF cleavage protease (ADAMTS-13) activity. Aortic stenosis (AS) may be complicated by acquired...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH11-12-0803
更新日期:2012-07-01 00:00:00
abstract::Von Willebrand factor (vWF) is synthesized by human endothelial cells and megakaryocytes as a large precursor, the pre-provWF, which is finally cleaved into the propolypeptide of vWF (pp-vWF) and the mature vWF. We have purified in parallel the pp-vWF and the GP IIb-IIIa from porcine platelets. The N-terminus comparat...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1998-10-01 00:00:00
abstract::[This corrects the article DOI: 10.1160/TH14-06-0547.]. ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,已发布勘误
doi:10.1160/TH17040001
更新日期:2017-04-03 00:00:00
abstract::We studied a murine monoclonal antibody (211 A6) to von Willebrand factor (vWF) with a view to investigating structure-relationship of plasma vWF. The specificity of this antibody has been substantiated by ELISA tests and indirect immunofluorescence. It reacts with purified vWF, normal plasma but not with plasma or pl...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1987-06-03 00:00:00
abstract::A disintegrin and metalloproteases (ADAMs) are membrane-bound enzymes responsible for the shedding or cleavage of various cell surface molecules, such as adhesion molecules, cytokines/chemokines and growth factors. This shedding can result in the release of soluble proteins that can exert agonistic or antagonistic fun...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,评审
doi:10.1055/s-0038-1660479
更新日期:2018-07-01 00:00:00
abstract::In hereditary angioedema (HAE), normal C1-inhibitor (C1-INH) is low and the contact system activated. Recently, the findings of a tissue factor mutant selectively deficient in promoting the conversion of FVII to FVIIa, but with retained cofactor for FVIIa, made it possible to examine reliably the pre-existing content ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1995-10-01 00:00:00
abstract::Antithrombin (AT) is a serine protease inhibitor that regulates the activity of coagulation proteases of both intrinsic and extrinsic pathways. We identified an AT-deficient patient with a heterozygous Thr90Ser (T90S) mutation who experiences recurrent venous thrombosis. To understand the molecular basis of the clotti...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1055/s-0040-1710590
更新日期:2020-07-01 00:00:00
abstract::Platelets from a patient with an acquired hemorrhagic disorder had a severely impaired response to collagen, whereas platelet aggregation to other agonists and coagulations tests were normal. No abnormalities of the patient's platelet membrane glycoproteins (GP) were seen. Treatment of the patient with immunosuppressi...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1990-08-13 00:00:00
abstract::Helicobacter pylori (H. pylori) infection is associated with peptic ulcer disease and gastric cancer. The eradication of H. pylori is of special interest in patients with congenital bleeding disorders, for whom treatment of gastrointestinal hemorrhage with factor concentrates is costly. The prevalence of H. pylori var...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2003-04-01 00:00:00
abstract::Viper venoms contain a variety of platelet binding proteins including those which bind to platelet GPIb/GPIX. Most of these proteins inhibit von Willebrand factor mediated platelet agglutination. Here we report the primary structures of unique members of this family, alboaggregins A and B, isolated from Trimeresurus a...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1998-03-01 00:00:00