Abstract：
:Despite years of research and efforts to translate stroke research to clinical therapy, ischaemic stroke remains a major cause of death, disability, and diminished quality of life. Primary and secondary preventive measures combined with improved quality of care have made significant progress. However, no novel drug for ischaemic stroke therapy has been approved in the past decade. Numerous studies have shown beneficial effects of activated protein C (APC) in rodent stroke models. In addition to its natural anticoagulant functions, APC conveys multiple direct cytoprotective effects on many different cell types that involve multiple receptors including protease activated receptor (PAR) 1, PAR3, and the endothelial protein C receptor (EPCR). Application of molecular engineered APC variants with altered selectivity profiles to rodent stroke models demonstrated that the beneficial effects of APC primarily require its cytoprotective activities but not its anticoagulant activities. Extensive basic, preclinical, and clinical research provided a compelling rationale based on strong evidence for translation of APC therapy that has led to the clinical development of the cytoprotective-selective APC variant, 3K3A-APC, for ischaemic stroke. Recent identification of non-canonical PAR1 and PAR3 activation by APC that give rise to novel tethered-ligands capable of inducing biased cytoprotective signalling as opposed to the canonical signalling provides a mechanistic explanation for how APC-mediated PAR activation can selectively induce cytoprotective signalling pathways. Collectively, these paradigm-shifting discoveries provide detailed insights into the receptor targets and the molecular mechanisms for neuroprotection by cytoprotective-selective 3K3A-APC, which is currently a biologic drug in clinical trials for ischaemic stroke.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Mosnier LO,Zlokovic BV,Griffin JHdoi
10.1160/TH14-05-0448subject
Has Abstractpub_date
2014-11-01 00:00:00pages
883-92issue
5eissn
0340-6245issn
2567-689Xpii
14-05-0448journal_volume
112pub_type
杂志文章,评审abstract：:Recent progress in the understanding of thrombus formation has suggested an important role of glycoprotein (GP)VI. In contrast to its pivotal role in collagen-induced platelet activation, it has been suggested that its blockade does not induce massive bleeding tendency. To demonstrate the dissociation between inhibito...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2006-08-01 00:00:00
abstract：:Macrophages are highly heterogeneous and plastic cells. They were shown to play a critical role in all stages of atherogenesis, from the initiation to the necrotic core formation and plaque rupture. Lesional macrophages primarily derive from blood monocyte, but local macrophage proliferation as well as differentiation...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
doi：10.1160/TH16-08-0593
更新日期：2017-01-05 00:00:00
abstract：:Thrombopoietin is produced at a constant rate by the liver and kidney and is removed from the circulation upon binding and subsequent uptake via the Tpo receptor, c-Mpl, expressed by platelets and mega-karyocytes. Apart from uptake, this study shows that platelets can also function as a storage pool for Tpo. Upon stim...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2000-06-01 00:00:00
abstract：:Antiphospholipid syndrome (APS) is an acquired thrombophilia with an uncertain role in the development of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess the association of APS with the clinical phenotype of CTEPH. We retrospectively reviewed data of CTEPH patients referred to our center. Cli...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1055/s-0039-1692428
更新日期：2019-09-01 00:00:00
abstract：:The salivary complex of the leech Haementeria depressa produces potent anticoagulant components. Among them, a protein named lefaxin inhibits factor Xa (FXa). Lefaxin was purified to homogeneity from dissected salivary complexes by gel filtration in Sephadex G-150 followed by two ion exchange chromatography steps in M...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1999-11-01 00:00:00
abstract：:Amniotic fluid inhibited the fibrinolytic, amidolytic and esterolytic activity of urokinase. Kinetic studies with AGLMe demonstrated non-competitive inhibition. A major part of the inhibitory activity could be separated from alpha 1-antitrypsin by ion-exchange chromatography on DEAE-Sephadex A-50. Plasminogen activato...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1980-08-29 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：:Multiple clinical trials have proven that thrombolytic therapy is an effective treatment for acute myocardial infarction. Spontaneous intracranial hemorrhage (ICH) occurs in a small percentage of patients as a result of the treatment. The etiology of the ICH is unknown and there is currently no established experimenta...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1996-05-01 00:00:00
abstract：:Accumulation of the newly formed 14C-cyclic adenosine 3',5'-monophosphate (cyclic AMP) was found in the P1 (1.0) fraction, i.e. a platelet plasma membrane fraction which was obtained from 14C-adenine-labeled platelets. On the other hand, total cyclic AMP as determined simultaneously was located mainly in the platelet ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1983-02-28 00:00:00
abstract：:Binding of von Willebrand factor (vWF) to a variety of extracellular matrix (ECM) components and to platelet glycoprotein (GP) Ib-IX-V complex is important in mediating platelet adhesion and aggregation in the early stage of hemostasis. We previously purified a potent antithrombotic protein, named crotalin, functional...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2001-12-01 00:00:00
abstract：:Washed human platelets have been labeled with either 32Pi or glycerol-1-14C and the distribution of the label in the phospholipids determined. 32Pi was introduced primarily into polyphosphoinositides, i.e. di- and triphosphoinositide, whereas the label from glycerol which indicates de novo synthesis of lipid molecules...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1976-04-30 00:00:00
abstract：:Effects of estradiol, progesterone, cortisol, thrombophlebitis and typhoid vaccine on the synthesis and catabolism of antithrombin III (AT) in dogs were studied, using I-125-labeled AT (I-125-AT) as a tracer. Five dogs were used for each study. A single intramuscular injection of 20 mg estradiol caused a 20% decrease ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1977-02-28 00:00:00
abstract：:Recent investigations have revealed the crucial role of von Willebrand factor (vWF) in platelet thrombus formation under flow conditions. The plasma concentrations of vWF were measured together with various hemodynamic and hemostatic parameters in 51 cases of acute myocardial infarction. In 10 randomly selected cases,...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2000-08-01 00:00:00
abstract：:Microangiopathy and disseminated platelet aggregation have been reported in thrombotic thrombocytopenic purpura (TTP) and pregnancy-induced hypertension (PIH). Since unusually large von Willebrand factor (vWF) multimers have been implicated in the evolvement of TTP, we analyzed factor VIII/vWF parameters in patients w...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1989-09-29 00:00:00
abstract：:Endothelial cell protein C receptor (EPCR) enhances the generation of activated protein C (APC) by the thrombin-thrombomodulin complex. A soluble form of EPCR (sEPCR), which is generated by metalloprotease activity, is present in plasma. The distribution of sEPCR levels in healthy populations is bimodal. Previously, w...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH03-10-0657
更新日期：2004-05-01 00:00:00
abstract：:Glu-plasminogen binds to platelets; the monocytoid line, U937, and the human fetal fibroblast line, GM1380 bind both plasminogen and its activator, urokinase. This study assesses the interaction of these fibrinolytic proteins with circulating human blood cells. Plasminogen bound minimally to red cells but bound satura...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1987-10-28 00:00:00
abstract：:Fibrinogen degradation products were investigated for leukocyte chemotactic activity and for enhancement of vascular permeability. Both activities increased progressively with plasmin digestion of fibrinogen. Active fragments were partially purified from 24 hr-plasmin digests. Molecular weights of the permeability inc...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1981-02-23 00:00:00
abstract：:Enhanced adhesion of sickle erythrocytes to the vascular endothelium and subendothelial matrix is fundamental to the development of vascular occlusion in sickle cell disease. Erythrocyte membrane sulfatide is implicated in the pathogenesis of vasoocclusive crises in sickle cell disease (SCD) patients. Because previous...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH10-11-0716
更新日期：2011-06-01 00:00:00
abstract：:We have previously reported that platelets from bleeding Simmental cattle do not aggregate in vitro in response to ADP, collagen and calcium ionophore A23187, though calcium mobilization and myosin light chain phosphorylation do occur. The aggregation abnormality, measured by aggregometry, was ascribed to abnormal cyt...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1996-12-01 00:00:00
abstract：:This study examines the relationship between plasma Plasminogen Activator Inhibitor-1 (PAI-1) activity and the PAI-1 4G/5G polymorphism, and their association with the risk of myocardial infarction (MI). Furthermore, this study explores whether a high level of PAI-1 or whether the PAI-1 4G/5G polymorphism synergistica...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2003-06-01 00:00:00
abstract：:This study was performed to follow up on the observation that gelatinase A (MMP-2) deficiency impairs adipose tissue development in mice. The aim was to evaluate the role of its functional homologue gelatinase B (MMP-9) in adipose tissue growth. MMP-9 antigen levels were determined in lean and in obese women before an...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH09-10-0739
更新日期：2010-07-01 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：:Multifunctional proteins, e.g. high molecular weight kininogen (HK, 120 kDa) and the homotrimer, thrombospondin (TSP, 540 kDa), which have more than one domain on a single polypeptide chain, are particularly well-suited to be structural elements of extracellular matrices because of their ability to bind to several mac...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1994-07-01 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：:Wound healing is a complicated biological process that consist of partially overlapping inflammatory, proliferation and tissue remodelling phases. A successful wound healing depends on a proper activation and subsequent termination of the inflammatory phase. The failure to terminate the inflammation halts the completi...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH15-08-0653
更新日期：2016-05-02 00:00:00
abstract：BACKGROUND:Preliminary evidence suggests that use of antipsychotic drugs is associated with an increased risk of venous thromboembolism. OBJECTIVE:To evaluate the relationship between antipsychotic or antidepressant drug use and venous thromboembolism among adults aged 65 years and older. DESIGN:Retrospective cohort ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2002-08-01 00:00:00
abstract：:Various tests were evaluated for their capacity to differentiate between platelet suspensions with different degrees of cell damage. Those suspensions were prepared by simultaneous isolation of platelets from the same platelet-rich plasma (PRP) using the following procedures: 1. centrifugation at 4 degrees C with EDTA...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1978-02-28 00:00:00
abstract：:Growing evidence indicates that rheumatoid arthritis (RA) is associated with an increased risk for thromboembolic cardiovascular events. We investigated thrombin generation profiles in RA patients and their dependence on plasma factor/inhibitor composition. Plasma factor (F) compositions (II, V, VII, VIII, IX, X), ant...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH10-02-0091
更新日期：2010-08-01 00:00:00
abstract：:The increase in nitric oxide (NO) production in lipopolysaccharide (LPS)-induced sepsis is thought to contribute to the development of shock. However, NO could also play an antithrombotic role. Little is known about the modulating effect of NO on the endothelial overexpression and production of tissue factor (TF) and ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2002-12-01 00:00:00
abstract：:The presence of lupus anticoagulant (LA) predisposes to fetal loss and to venous and arterial thrombosis; however, a subgroup of women is unaffected by pregnancy loss. Currently, no predictive markers are available for the identification of women positive for LA at increased risk for pregnancy loss. It was the aim of ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2006-05-01 00:00:00
