Abstract：
:Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is mainly caused by dominant-negative mutations in the multimeric protein von Willebrand factor (VWF). These mutations may either result in quantitative or qualitative defects in VWF. VWF is an endothelial protein that is secreted to the circulation upon endothelial activation. Once secreted, VWF multimers bind platelets and chaperone coagulation factor VIII in the circulation. Treatment of VWD focuses on increasing VWF plasma levels, but production and secretion of mutant VWF remain uninterrupted. Presence of circulating mutant VWF might, however, still affect normal hemostasis or functionalities of VWF beyond hemostasis. We hypothesized that inhibition of the production of mutant VWF improves the function of VWF overall and ameliorates VWD phenotypes. We previously proposed the use of allele-specific small-interfering RNAs (siRNAs) that target frequent VWF single nucleotide polymorphisms to inhibit mutant VWF. The aim of this study is to prove the functionality of these allele-specific siRNAs in endothelial colony-forming cells (ECFCs). We isolated ECFCs from a VWD type 2A patient with an intracellular multimerization defect, reduced VWF collagen binding, and a defective processing of proVWF to VWF. After transfection of an allele-specific siRNA that specifically inhibited expression of mutant VWF, we showed amelioration of the laboratory phenotype, with normalization of the VWF collagen binding, improvement in VWF multimers, and enhanced VWF processing. Altogether, we prove that allele-specific inhibition of the production of mutant VWF by siRNAs is a promising therapeutic strategy to improve VWD phenotypes.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
de Jong A,Dirven RJ,Boender J,Atiq F,Anvar SY,Leebeek FWG,van Vlijmen BJM,Eikenboom Jdoi
10.1055/s-0040-1715442subject
Has Abstractpub_date
2020-11-01 00:00:00pages
1569-1579issue
11eissn
0340-6245issn
2567-689Xjournal_volume
120pub_type
杂志文章abstract：:Type I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF cont...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1993-02-01 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：:Normal adults have very few circulating endothelial cells (CECs) in their blood, but increased levels have been shown in association with conditions associated with endothelial damage such as myocardial infarction and stroke. As atrial fibrillation (AF) is associated with a hypercoagulable state and abnormalities of p...
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
abstract：:Expression of isolated beta integrin cytoplasmic domains in cultured endothelial cells was reported to induce cell detachment and death. To test whether cell death was the cause or the consequence of cell detachment, we expressed isolated integrin beta1 cytoplasmic and transmembrane domains (CH1) in cultured human umb...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2005-11-01 00:00:00
abstract：:The glycosaminoglycan, heparan sulfate (HS) is composed of alternating units of hexuronic acid and glucosamine, that are variously sulfate-substituted at different positions. Proteoglycans carrying HS chains are ubiquitously expressed at cell surfaces and in the extracellular matrix. The structures of these chains are...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
doi：
更新日期：2007-07-01 00:00:00
abstract：:Our aim was to demonstrate that the sequential use of the Verigene® rapid CYP2C19 test for genetic profiling and the VerifyNowTM bedside test for platelet function measurement in ACS patients may optimise P2Y12 inhibition. "Rapid" (CYP2C19*1/*1 or CYP2C19*17 carriers, n=211) and "slow" metabolisers (CYP2C19*2 carriers...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,多中心研究
doi：10.1160/TH15-05-0394
更新日期：2016-01-01 00:00:00
abstract：:The methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 C→T polymo...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH11-12-0899
更新日期：2012-09-01 00:00:00
abstract：:Primary prevention is the key to managing a significant proportion of the burden of venous thromboembolism (VTE), defined as deep venous thrombosis (DVT) or pulmonary embolism (PE). This is because VTE may lead to sudden death or are often misdiagnosed and therefore treatment is not feasible. Primary prevention usuall...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
doi：10.1160/TH14-10-0823
更新日期：2015-06-01 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：:In a placebo-controlled trial healthy volunteers and patients with hyperlipoproteinemias types II and IV received orally vitamin E at doses of 300 mg and 600 mg daily for 2 weeks. Serum tocopherol levels increased two-fold, but serum concentrations of total lipids, cholesterol, triglycerides, ceruloplasmin and transfe...
journal_title：Thrombosis and haemostasis
pub_type： 临床试验,杂志文章
doi：
更新日期：1985-08-30 00:00:00
abstract：:Accumulating evidence suggests an immune-modulatory role for platelets (PLT) and PLT-derived microvesicles. In particular, ectosomes, i.e. vesicles budding from PLT surface, have been shown to exert immunosuppressive activities on phagocytes. Here we investigated the effects mediated by PLT-derived ectosomes (PLT-Ecto...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH14-03-0281
更新日期：2014-12-01 00:00:00
abstract：:The walls of rabbit mesenteric arterioles and venules (diameter 20 to 40 microns) were punctured with glass micropipets (tip diameter 6 to 8 microns). Thromboembolic reactions resulting from this standardized, small mechanical vessel wall injury could be quantified in vivo with the use of intravital video-microscopy. ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1988-02-25 00:00:00
abstract：:We investigated the molecular basis of hypofibrinogenaemia in a woman with a history of recurrent, pregnancy-associated bleeding, and miscarriage. She had a Clauss fibrinogen of 0.9 mg/ml and SDS PAGE of purified fibrinogen showed a normal pattern of chains. However careful inspection of reverse phase chain separation...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2000-09-01 00:00:00
abstract：:High physiological concentrations of plasma vasopressin (aVP) when achieved by infusion cause an increase in plasma factor VIII coagulant activity and shortening of the euglobulin clot lysis time (ECLT). To investigate the effects of aVP on components of the fibrinolytic pathway and on thrombin generation, 9 healthy v...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1989-04-25 00:00:00
abstract：:Tamoxifen is a known anti-cancer drug and established estrogen receptor modulator. Few clinical studies have earlier implicated the drug in thrombotic complications attributable to lower anti-thrombin and protein S levels in plasma. However, action of tamoxifen on platelet signalling machinery has not been elucidated ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH11-03-0178
更新日期：2011-10-01 00:00:00
abstract：:Venous thromboembolic (VTE) complications in children and adolescents with acute lymphoblastic leukaemia (ALL) and T or B cell lymphoblastic lymphoma (T/B cell LL) can result not only in life-threatening acute complications but also contribute to significant long-term sequelae. The PREVAPIX-ALL study is an open-label ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,多中心研究,随机对照试验
doi：10.1055/s-0039-1679938
更新日期：2019-05-01 00:00:00
abstract：:We studied the HR2 haplotype of the factor V gene in a case-control study for venous thrombosis including 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched healthy controls (Leiden Thrombophilia Study, LETS). We investigated both the original His1299Arg (A4070G) polymorphism and the Met385Thr...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2000-04-01 00:00:00
abstract：:Platelet counts were evaluated in 714 patients with advanced non-small cell lung cancer (N-SCLC), small cell carcinoma of the lung (SCCL), and colon cancer entered to a clinical trial. Patients had not received prior chemotherapy. Platelet counts were not different in patients who had received radiation therapy prior ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1990-12-28 00:00:00
abstract：:A previous study of neurosurgical patients demonstrated an imbalance between thrombin and plasmin action following surgery. The present study was designed to determine the effect of intermittent pneumatic calf compression on postoperative enzyme activity. Fibrinopeptide A (FPA) and B beta 1-42 levels, reflecting throm...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1986-10-21 00:00:00
abstract：:Lupus anticoagulants (LA) are immunoglobulins directed to either prothrombin or Beta-2-glycoprotein 1(beta1GPI) bound to phospholipids. Most patients with LA have both beta2GPI- and prothrombin-dependent antibodies. Several recent reports have shown that LA is more strongly associated with thrombosis than anticardioli...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,多中心研究
doi：
更新日期：1999-06-01 00:00:00
abstract：:Thromboembolic complications have been attributed to the use of radiographic contrast media (CM) during interventional procedures for arterial revascularization. However, due to the low frequency of adverse events, comparisons between different CM have been difficult to perform, although it has been suggested that ion...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2001-03-01 00:00:00
abstract：:Factor V Leiden is a procoagulant mutation associated with venous and arterial thrombosis and pregnancy complications. Its high prevalence of 5% in Caucasians suggests that there are evolutionary benefits as well. Carriers are indeed reported to have various advantageous phenotypes related to haemostasis, inflammation...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
doi：10.1160/TH13-02-0115
更新日期：2013-07-01 00:00:00
abstract：:This study was carried out in order to compare the coagulation balance in patients with colorectal cancer before and after surgical removal of tumor with an age matched non-malignancy control group. Furthermore, it was studied whether preoperative coagulation state in cancer patients was correlated to the postoperativ...
journal_title：Thrombosis and haemostasis
pub_type： 临床试验,杂志文章
doi：
更新日期：1996-10-01 00:00:00
abstract：:An alternative method of uniting small diameter vessels to obtain tissue union while limiting the thrombogenic effect of suture placement at a vessel anastomosis involves the use of a thrombin based fibrin glue as a surgical sealant. This investigation addresses whether the in vitro application of a thrombin based glu...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1997-08-01 00:00:00
abstract：:Activated protein C (APC)-mediated inactivation of factor VIII (FVIII) correlates with cleavage at either Arg336 and/or Arg562. To elucidate the APC cleavage requirements for inactivation of FVIII, APC cleavage site mutants in FVIII (R336I, R562K and R336I/R562K) were made by site-directed mutagenesis. Analysis of the...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1998-03-01 00:00:00
abstract：:It is known that thrombosis is a leading cause of vascular access failure and that the formation of thrombus requires platelets. The activation of platelets induces the increase in intracellular Ca 2(+) levels ([Ca(2+)](i)) leading to aggregation and thrombosis. We compared the platelet [Ca(2+)](i) before and after st...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH04-01-0048
更新日期：2004-09-01 00:00:00
abstract：:Vascular smooth muscle cell (VSMC) proliferation occurs in vascular obstructive events such as atherosclerosis and restenosis. We previously showed that Notch receptors are induced in smooth muscle cells during vascular remodeling. Our goal was to determine the mechanisms employed by Notch signaling to regulate prolif...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH06-04-0224
更新日期：2006-09-01 00:00:00
abstract：:Platelet activation may contribute to the increased risk of thrombotic complications in patients with antiphospholipid antibodies (aPL). The increased urinary excretion of 11-dehydro-thromboxane B2 (11-DH-TXB2) reported in patients with lupus anticoagulant (LA) and/or anticardiolipin antibodies (aCL) reflects in vivo ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1998-01-01 00:00:00
abstract：:Increased fibrinogen concentration is a well known phenomenon following acute ischemic stroke. However, the natural course of this hyperfibrinogenemia is uncertain. We aimed to clarify whether it is of a transient or more persistent nature in patients who harbor an underlying morbid biology of atherothrombo-inflammati...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH07-08-0484
更新日期：2008-01-01 00:00:00
abstract：:Alteplase is standard therapy for patients with acute, massive pulmonary embolism. The novel plasminogen activator desmoteplase displays high fibrin specificity and selectivity for fibrinbound plasminogen. In a preclinical model desmoteplase was twice as potent with a shorter lysis time and lower reocclusion rate. We ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,多中心研究,随机对照试验
doi：
更新日期：2009-03-01 00:00:00
