Abstract:
:We have discovered a novel small-molecule (3-phosphinoylpropionic acid) inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa), BX 528, which had an IC (50) of 2 nM in an enzymatic assay and 50 nM in an in-vitro clot lysis assay, with 3,500- to 35,000-fold selectivity against other carboxypeptidases, such as CPN, CPZ and CPD, and 5- and 12-fold selectivity against CPE (CPH) and CPB, respectively. At 10 micro M, BX 528 had no significant activity (<50% inhibition or antagonism) in a panel of 137 enzymes and receptors. It had no effects on blood coagulation and platelet aggregation up to 300 and 10 micro M, respectively. The plasma half-life following intravenous administration was 0.85 hours in rats and 4.5 hours in dogs. No significant metabolism was detected in human, dog or rabbit hepatic microsomes, and no significant inhibition of cytochrome P450 3A4 and 2D6 up to 30 micro M. No cytotoxic or cell proliferative effects were found in three hepatic and renal cell lines up to 300 micro M and no mutagenic activity was seen in the Ames II screen. There were no significant hemodynamic effects in rats and dogs up to 100 and 30 mg/kg with peak plasma drug concentrations of approximately 1,000 and 300 micro M, respectively. In an in-vivo complement activation model in guinea pigs, BX 528 showed minimal inhibition of plasma CPN activity up to 60 mg/kg with peak plasma concentrations up to 250 micro M. Thus, these data demonstrate that BX 528 is a novel, potent, selective and safe TAFIa inhibitor.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Wang YX,Zhao L,Nagashima M,Vincelette J,Sukovich D,Li W,Subramanyam B,Yuan S,Emayan K,Islam I,Hrvatin P,Bryant J,Light DR,Vergona R,Morser J,Buckman BOsubject
Has Abstractpub_date
2007-01-01 00:00:00pages
45-53issue
1eissn
0340-6245issn
2567-689Xpii
07010045journal_volume
97pub_type
杂志文章abstract::In patients with deep vein thrombosis (DVT), the factors which predispose to concomitant symptomatic pulmonary embolism (PE) have remained uncertain. From a prospective cohort of 5,451 consecutive patients with ultrasound-confirmed DVT, we analyzed 4,211 patients with a known status for presence (n=639) or absence (n=...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH04-09-0587
更新日期:2005-03-01 00:00:00
abstract::Two novel polymorphisms were identified in the factor V gene by direct sequencing of intronic areas. One of them, located in intron 9, is the marker closest to the Leiden mutation ever described, whereas the other, in intron 16, displays a rare allele invariantly associated to the mutation. Allele-specific amplificati...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1997-09-01 00:00:00
abstract::The aim of this study was to investigate the anti-thrombotic effects of an inhibitor of the plasminogen activator inhibitor-1 (PAI-1) in rats given endotoxin. In studies in vitro, PRAP-1, a Fab-fragment of a polyclonal antibody against human PAI-1, was shown to inhibit PAI-1 activity in rat plasma as well as to stimul...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1996-01-01 00:00:00
abstract::Haemorrhagic metalloproteinases from Bothrops jararaca and other venoms degrade vessel-wall and plasma proteins involved in platelet plug and fibrin clot formation. These enzymes also cause proteolytic digestion of fibrinogen which has been suggested to cause defective platelet function. Fibrinogen degradation by jara...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1994-08-01 00:00:00
abstract::Thirty-three patients with acute iliofemoral thrombosis were randomly assigned to three treatment groups in a pilot dose-ranging study of thrombolytic therapy in deep vein thrombosis. One group received tissue culture urokinase in a dose of 2,200 I.U./kg/hr, and a second group in a dose of 1,100 I.U./kg/hr following a...
journal_title:Thrombosis and haemostasis
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1983-10-31 00:00:00
abstract::Cell accumulation is a prerequisite for adipose tissue inflammation. The leukocyte integrin Mac-1 (CD11b/CD18, αMβ2) is a classic adhesion receptor critically regulating inflammatory cell recruitment. Here, we tested the hypothesis that a genetic deficiency and a therapeutic modulation of Mac-1 regulate adipose tissue...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH16-07-0553
更新日期:2017-01-26 00:00:00
abstract::Factor X (FX) is a vitamin K-dependent serine protease zymogen that functions in both the extrinsic and intrinsic pathways of blood coagulation. In this study, the 5'-flanking region of the murine FX gene was analyzed to determine those elements that govern its transcriptional activity and regulation. Consistent with ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2000-12-01 00:00:00
abstract::Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein however the mechanisms by which Lp(a) promote the atherosclerotic process are not clear. The apolipoprotein(a) portion of Lp(a) shares partial homology with plasminogen, a finding that has stimulated numerous studies. Lp(a) binds to fibrin and the affinity between f...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,评审
doi:
更新日期:1995-07-01 00:00:00
abstract::Some correlations between plasma and platelet fatty acids (FA) were evaluated "ex vivo" in 94 normal subjects. The highest relationships between total FA from plasma and platelets were found for 18:1 (r = 0.74) and 18:2 (r = 0.67). Low correlations were obtained for free fatty acids (FFA). The most significant correla...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1984-12-29 00:00:00
abstract::We found that intracellular Ca2+ concentration ([Ca2+]i) increased during ristocetin-induced agglutination of aequorin loaded platelets resuspended in plasma. Chelation of extracellular Ca2+ had no effect on platelet clumping, but delayed and greatly reduced Ca2+ increase, indicating that it derived for the most part ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1995-04-01 00:00:00
abstract:INTRODUCTION:Rivaroxaban (RXA) is a direct oral factor Xa (Xa) antagonist with a short half-life and a fast onset and offset of effect. Before elective surgery, discontinuation is recommended with an interval of at least > 24 hours. In clinical practice, this is, however, not always sufficient to achieve a residual RXA...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1055/s-0038-1639585
更新日期:2018-05-01 00:00:00
abstract:BACKGROUND: Evaluation of thromboembolic risk is essential in anticoagulated atrial fibrillation (AF) patients. The CHA2DS2-VASc score is largely validated and recommended by most guidelines. The GARFIELD-AF Stroke score has been proposed as an alternative risk score. METHODS: We analyzed warfarin-treated patients fro...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1055/a-1333-4448
更新日期:2020-12-09 00:00:00
abstract::Circulating endothelial cells (CEC) are considered a promising marker to determine the extent of vascular damage. However, currently available and validated CEC enumeration assays are laborious, time consuming and costly, which limits their clinical utility. Here, we evaluated the feasibility of quantifying mRNA level...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH09-08-0594
更新日期:2010-08-01 00:00:00
abstract::Deep vein thrombosis (DVT) in children occurs primarily in the upper body venous system. This prospective diagnostic study compared bilateral venography and ultrasound for detection of DVT in the upper venous system in 66 children with acute lymphoblastic leukemia. Results were interpreted by central blinded adjudicat...
journal_title:Thrombosis and haemostasis
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:
更新日期:2002-04-01 00:00:00
abstract::Site directed mutagenesis was used to construct a t-PA variant that contains an additional glycosylation site in the first kringle domain (T103N) combined with a tetra-alanine substitution in the protease domain (KHRR 296-299 AAAA). This combination variant has a plasma clearance rate that is 4.5-fold slower in rats a...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1993-08-02 00:00:00
abstract::The cellular phospholipid, lysophosphatidic acid (LPA), released by activated platelets and fibroblasts or, at high levels, from ovarian and cervical carcinomas is a powerful serum mitogen that may modulate several signaling pathways in endothelial cells (EC). Hence, LPA could function in a paracrine manner during EC-...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1999-11-01 00:00:00
abstract::Echolucent carotid plaques are associated with higher risk for future ischemic cerebrovascular events (CVE) than echogenic plaques independent of the degree of stenosis. Elevated markers of thrombin generation are associated with atherosclerotic plaques and are increased in the acute and chronic phases of CVE. The pre...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH07-08-0493
更新日期:2008-03-01 00:00:00
abstract::Electrospray ionisation mass spectrometry was used to probe the structure of the new N-linked oligosaccharide in fibrinogen Kaiserslautern (gamma 380 Lys-->Asn). The mass increase of 2177 Da in the new beta chain indicated the attachment of a fully sialylated biantennary oligosaccharide on the new Asn residue; the exp...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1998-08-01 00:00:00
abstract::Although, the main physiological role of monocytes is attributed to innate immunity (that is, phagocytosis) and the development of tissue macrophages and dendritic cells, the pathophysiological role of these goes far behind these (simplistic) limits. Indeed, monocytes constitute a major source of blood tissue factor, ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,评审
doi:10.1160/TH09-01-0023
更新日期:2009-11-01 00:00:00
abstract::Antiphospholipid antibodies (aPL) have been associated with thrombosis and pregnancy losses in patients diagnosed with antiphospholipid syndrome (APS) and enhance thrombus formation in vivo in mice, but the mechanism of thrombosis by aPL is not completely understood. It has been proposed that aPL may affect endothelia...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2000-09-01 00:00:00
abstract::Fucoïdans catalyse thrombin inhibition by antithrombin (AT) and heparin cofactor II (HCII); their affinity for each serpin varies according to the seaweed species from which they are extracted, as well as their chemical composition and molecular weight. We extracted a homogeneous fucoïdan fraction from Ascophyllum nod...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1995-11-01 00:00:00
abstract::It is widely anticipated that large platelets are more reactive than small platelets. This was mainly shown in Ca2+-poor media albeit extracellular Ca2+ is utilized by platelets for activation. We determined the impact of extracellular Ca2+ on functional differences between large and small platelets in response to thr...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1055/s-0040-1712447
更新日期:2020-07-01 00:00:00
abstract::The effect of selective activation of platelet prostaglandin (PG) E2 receptor subtype EP2 or EP4 on platelet aggregation remains to be determined. In platelets prepared from wild-type mice (WT platelets), high concentrations of PGE2 inhibited platelet aggregation induced by U-46619, a thromboxane receptor agonist. How...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH10-01-0043
更新日期:2010-10-01 00:00:00
abstract::Platelet-rich plasma was obtained 24 hr after the race ended from athletes who ran in the London marathon. The platelets were only marginally less sensitive to adrenaline than were those of non-runners using conventional aggregation tests. However, the runners' platelets were much more sensitive to inhibition by prost...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1984-07-29 00:00:00
abstract::The effect of negatively-charged polymers, used in some artificial devices, on plasma clotting and kinin systems was studied in vitro using polyelectrolyte complexes. Contact activation was observed as an immediate, transient and surface-dependent phenomenon. After incubation of the plasma with the polymer a small dec...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1984-02-28 00:00:00
abstract::When adenosine diphosphate (ADP) is added to hirudinized platelet-rich plasma (PRP) in which the level of platelet cAMP has been pharmacologically elevated, there is an initial rapid fall in the level of cAMP brought about by inhibition of adenylate cyclase. This may be followed by a subsequent activation of adenylate...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1998-08-01 00:00:00
abstract::Local ISI calibration has been proposed to improve INR accuracy and inter-laboratory precision. We evaluated the affect of local PT calibration on INR precision and accuracy using six levels of frozen plasma calibrants prepared and pooled from normal donors and patients stabilized on sodium warfarin (coumarin) based o...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2002-01-01 00:00:00
abstract::Patients with atrial fibrillation at moderate to high risk of stroke are not always anticoagulated despite a lack of contraindications to vitamin K antagonists (VKAs) like warfarin. These patients are treated with aspirin, aspirin-clopidogrel combination therapy or even receive no thromboprophylaxis. The oral direct t...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,meta分析
doi:10.1160/TH10-10-0642
更新日期:2010-12-01 00:00:00
abstract::Recent clinical studies have shown that the interruption of platelet function appears to be effective for treatment of coronary occlusive diseases. For this purpose, a Fab fragment of humanized anti-platelet glycoprotein (GP) IIb/IIIa monoclonal antibody (YM 337) that exhibited an in vivo antithrombotic effect without...
journal_title:Thrombosis and haemostasis
pub_type: 临床试验,杂志文章
doi:
更新日期:1998-07-01 00:00:00
abstract::The Ig-ITIM superfamily member, PECAM-1 acts as a negative regulator of ITAM-signalling pathways in platelets involving GPVI/FcR gamma chain and Fc?RIIa. This negative feedback loop involves regulation of collagen and GPVI-dependent aggregation events, platelet-thrombus-growth on immobilised collagen under flow and Fc...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2006-12-01 00:00:00