Abstract:
:Primary immune thrombocytopaenia (ITP) is the most common haemorrhagic disease. Although most patients respond initially to mainstream therapies, such as corticosteroids, immunosuppressants or rituximab, a large proportion of patients fail to respond or relapse. These treatments only affect B lymphocytes or short-lived plasma cells, but not already existing long-lived plasma cells (LLPCs) which persistently secrete antibodies. We hypothesized that LLPCs may play a role in the corticosteroid-resistant or relapsed ITP patients, and bortezomib, a proteasome inhibitor, may act on plasma cells and offer a therapeutic effect. Although a significant difference in the proportion of CD19-CD38hiCD138+ total LLPCs was not observed by flow cytometry, a glycoprotein (GP) IIb/IIIa-specific enzyme-linked immunosorbent spot (ELISpot) assay of sorted CD19-CD138+ LLPCs confirmed the existence of anti-platelet antibody-secreting LLPCs in ITP patients in contrast to healthy controls. Moreover, the LLPCs could be eliminated in the presence of bortezomib by ELISpot assay, which was also confirmed by flow cytometry. Accordingly, a modified monoclonal antibody immobilization of platelet antigen assay of sorted CD19-CD138+ LLPCs revealed that the concentration of anti-platelet antibodies decreased remarkably when cultured with 0.25 ng/mL bortezomib for 5 days. The apoptosis assay demonstrated that bortezomib could induce apoptosis of LLPCs in a concentration-dependent manner. The proteasome activity assay showed that bortezomib significantly reduced the proteasome activity in sorted CD19-CD138+ LLPCs. Furthermore, in active ITP murine models, bortezomib eliminated LLPCs in vivo and alleviated thrombocytopaenia. We conclude that LLPCs participate in the pathogenesis of ITP and bortezomib may have potential as a novel therapeutic regimen.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Li G,Wang S,Li N,Liu Y,Feng Q,Zuo X,Li X,Hou Y,Shao L,Ma C,Gao C,Hou M,Peng Jdoi
10.1055/s-0038-1669921subject
Has Abstractpub_date
2018-10-01 00:00:00pages
1752-1764issue
10eissn
0340-6245issn
2567-689Xjournal_volume
118pub_type
杂志文章abstract::Autoantibodies to the zwitterionic phospholipid (PL), phosphatidylethanolamine (PE) have been described in patients with thrombotic diseases. Recently, we reported that many antiphosphatidylethanolamine antibodies (aPE) are not specific for PE per se, but are directed to plasma proteins which can bind PE, for example,...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::Factor VIII inhibitors in mild haemophilia are uncommon and the management of such patients is controversial. The development of a persistently high responding F VIII inhibitor in a mild haemophiliac is reported and the behaviour of the inhibitor discussed in the context of the various therapeutic regimes employed for...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1984-08-31 00:00:00
abstract::To identify whether genotype contributes to the difference in PAI-1 levels in type 1 and type 2 diabetic subjects and whether genotype relates to the development of retinopathy, a Hind III restriction fragment length polymorphism and two dinucleotide repeat polymorphisms were studied. In 519 Caucasian diabetic subject...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1994-06-01 00:00:00
abstract::Elucidation of the pathophysiological basis of platelet disorders in murine models requires a reliable method for the frequent determinations of platelet counts in individual mice. Here, we present a rapid, reproducible and accurate flow cytometric method for enumeration of platelets that involves fluorescent staining...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2001-08-01 00:00:00
abstract::Per cent aggregation, release and content of adenine nucleotides, and specific radioactivity were evaluated in citrated platelet-rich plasma (PRP) prepared from paired samples of maternal and cord blood. Platelets of newborn infants aggregated normally in response to highdose ADP (20 muM), strong collagen suspensions,...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1976-08-31 00:00:00
abstract::Increased red blood cell distribution width (RDW), which is a marker of anisocytosis, is associated with mortality and cardiovascular events in the general population and in patients with heart failure or coronary heart disease. We investigated whether RDW in acute cerebral infarction is predictive of functional outco...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH12-03-0165
更新日期:2012-08-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1985-04-22 00:00:00
abstract::The effects of G4120, a cyclic Arg-Gly-Asp (RGD) containing peptide which inhibits fibrinogen binding to the platelet receptor GPIIb/IIIa, on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) were investigated in a combined arterial and venous thrombosis model in heparinized dogs. The arterial th...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1992-06-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH03-02-0106
更新日期:2003-09-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH05-02-0093
更新日期:2005-10-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1989-11-24 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH17-02-0087
更新日期:2017-08-30 00:00:00
abstract::A nutritionally induced obesity model was used to investigate the modulation of fibrinolytic and gelatinolytic activity during the development of adipose tissue. Five week old male mice were fed a standard fat diet (SFD, 13% kcal as fat) or a high fat diet (HFD, 42% kcal as fat) for up to 15 weeks. The HFD resulted in...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2002-08-01 00:00:00
abstract::The availability of mice with tissue-specific expression of recombinase Cre is the limiting step for a successful gene targeting by the Cre-LoxP methodology. This work aimed at generating transgenic mice with restricted expression of recombinase Cre in megakaryocytes and platelets, driven by the promoter of the αIIb g...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH10-06-0378
更新日期:2011-01-01 00:00:00
abstract::The fibrinolytic system was studied in 96 patients with type I diabetes mellitus. Patients were grouped according to their degree of retinopathy; 38 patients with no evidence of retinopathy, 28 patients with background retinopathy and 30 patients with proliferative retinopathy. Thirty healthy individuals served as con...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1992-10-05 00:00:00
abstract::In wound repair, fibrin has a multiplicity of activities, some of which are intrinsic to the protein itself and some attributable to other blood constituents associated with the fibrin clot. Fibrin sealants, which have been approved for hemostasis in the US and Europe, are occasionally used wounds to promote healing. ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,评审
doi:10.1160/TH03-08-0526
更新日期:2003-12-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,评审
doi:10.1160/TH09-05-0323
更新日期:2009-12-01 00:00:00
abstract::Sequential treatment of arterial occlusions of the leg with porcine plasmin and low dose streptokinase results in a strong systemic proteolysis as already seen in deep leg vein thrombosis. In 31 of 45 patients the blood flow through major arterial segments could be restored. Thrombolytic success is possible within the...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1982-10-29 00:00:00
abstract::Forty-two patients with total occlusion of a coronary vessel were treated with intracoronary fibrinolytic agents. Four therapeutic protocols were compared: group I received streptokinase (SK) as a continuous infusion; group II and III received SK as a bolus at different doses and group IV received lysplasminogen (Pg) ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1983-12-30 00:00:00
abstract::Nitric oxide (NO) is a signaling molecule of major importance modulating not only the function of the vascular wall but also that of blood cells, such as platelets and leukocytes. The synthesis of NO in the circulation has been attributed mainly to the vascular endothelium. Red blood cells (RBC) have been demonstrated...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章,评审
doi:
更新日期:2007-11-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2007-03-01 00:00:00
abstract::By a method of counting single platelets in diluted whole blood, platelet aggregates were quantified ex-vivo. Four groups: 20 thrombotic patients, 10 non-thrombotic patients, 10 healthy old controls and 10 healthy young controls were included in the study. Using a 19 gauge needle, with and without tubing, venous blood...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1986-08-20 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2001-03-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH09-05-0290
更新日期:2010-01-01 00:00:00
abstract::Intraoperative high-dose aprotinin administration has been shown to reduce the intra-and postoperative blood loss in cardiac surgery. The haemostatic effect has been attributed to platelet preserving properties and to inhibition of contact activation reducing thrombotic and fibrinolytic activity during and after cardi...
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:1995-05-01 00:00:00
abstract::Lysyl oxidase (LOX) is an extracellular matrix-modifying enzyme that seems to play a critical role in vascular remodelling. However, the lack of viable LOX-deficient animal models has been an obstacle to deep in LOX biology. In this study we have developed a transgenic mouse model that over-expresses LOX in vascular s...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:10.1160/TH14-01-0024
更新日期:2014-10-01 00:00:00
abstract::Clots formed from platelet rich plasma were found to be lysed more readily by low concentrations of pro-urokinase (pro-UK) than clots formed from platelet poor plasma. This was not a non-specific effect since the reverse occurred with tissue plasminogen activator. A mechanical explanation due to platelet-mediated clot...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1994-03-01 00:00:00
abstract::The Bernard-Soulier syndrome (BSS) is characterized by thrombocytopenia with giant platelets, a prolonged bleeding time with defective platelet adhesion to the subendothelium related to a defect in platelet membrane glycoprotein Ib (GPIb) and a decreased prothrombin consumption. The mechanism of the latter abnormality...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1997-02-01 00:00:00
abstract::Atherosclerotic plaque rupture may trigger the formation of mural thrombus. This thrombus formation is apparently affected by very high and complex shear conditions introduced by the luminal narrowing (stenosis) of the atheroma. To study the impact of such blood flow behaviour on thrombus formation we employed a model...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1996-04-01 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