Recombinant GPVI-Fc added to single or dual antiplatelet therapy in vitro prevents plaque-induced platelet thrombus formation.

Abstract:

:The efficiency of current dual antiplatelet therapy might be further improved by its combination with a glycoprotein (GP) VI-targeting strategy without increasing bleeding. GPVI-Fc, a recombinant dimeric fusion protein binding to plaque collagen and concealing binding sites for platelet GPVI, acts as a lesion-focused antiplatelet drug, and does not increase bleeding in vivo. We investigated, whether GPVI-Fc added in vitro on top of acetylsalicylic acid (ASA), the P2Y12 antagonist ticagrelor, and the fibrinogen receptor antagonist abciximab alone or in combination would increase inhibition of platelet activation by atherosclerotic plaque. Under static conditions, GPVI-Fc inhibited plaque-induced platelet aggregation by 53 %, and increased platelet inhibition by ASA (51 %) and ticagrelor (64 %) to 66 % and 80 %, respectively. Under arterial flow, GPVI-Fc inhibited plaque-induced platelet aggregation by 57 %, and significantly increased platelet inhibition by ASA (28 %) and ticagrelor (47 %) to about 81 % each. The triple combination of GPVI-Fc, ASA and ticagrelor achieved almost complete inhibition of plaque-induced platelet aggregation (93 %). GPVI-Fc alone or in combination with ASA or ticagrelor did not increase closure time measured by the platelet function analyzer (PFA)-200. GPVI-Fc added on top of abciximab, a clinically used anti-fibrinogen receptor antibody which blocks platelet aggregation, strongly inhibited total (81 %) and stable (89 %) platelet adhesion. We conclude that GPVI-Fc added on top of single or dual antiplatelet therapy with ASA and/or a P2Y12 antagonist is likely to improve anti-atherothrombotic protection without increasing bleeding risk. In contrast, the strong inhibition of platelet adhesion by GPVI-Fc in combination with GPIIb/IIIa inhibitors could be harmful.

journal_name

Thromb Haemost

authors

Mojica Muñoz AK,Jamasbi J,Uhland K,Degen H,Münch G,Ungerer M,Brandl R,Megens R,Weber C,Lorenz R,Siess W

doi

10.1160/TH16-11-0856

subject

Has Abstract

pub_date

2017-08-01 00:00:00

pages

1651-1659

issue

8

eissn

0340-6245

issn

2567-689X

pii

16-11-0856

journal_volume

117

pub_type

杂志文章
  • Effect of Additional Treatments Combined with Conventional Therapies in Pregnant Patients with High-Risk Antiphospholipid Syndrome: A Multicentre Study.

    abstract::The effect of additional treatments combined with conventional therapy on pregnancy outcomes was examined in high-risk primary antiphospholipid syndrome (PAPS) patients to identify the most effective treatment strategy. The study's inclusion criteria were (1) positivity to lupus anticoagulant alone or associated with ...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章,多中心研究

    doi:10.1055/s-0038-1632388

    authors: Ruffatti A,Tonello M,Hoxha A,Sciascia S,Cuadrado MJ,Latino JO,Udry S,Reshetnyak T,Costedoat-Chalumeau N,Morel N,Marozio L,Tincani A,Andreoli L,Haladyj E,Meroni PL,Gerosa M,Alijotas-Reig J,Tenti S,Mayer-Pickel K,Simc

    更新日期:2018-04-01 00:00:00

  • Effect of calcium and synthetic peptides on fibrin polymerization.

    abstract::Human fibrinogen was subjected to limited proteolytic attack by thrombin, batroxobin or Agkistrodon contortrix thrombin-like enzyme, yielding desAB-, desA- or desB-fibrin monomers, respectively. Turbidity curves demonstrated that, with all three enzymes, the polymerization process was strongly accelerated by increasin...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Furlan M,Rupp C,Beck EA,Svendsen L

    更新日期:1982-04-30 00:00:00

  • Local inflammation is associated with aortic thrombus formation in abdominal aortic aneurysms. Relationship to clinical risk factors.

    abstract::Intraluminal thrombus formation in aortic abdominal aneurysms (AAA) is associated with adverse clinical prognosis. Interplay between coagulation and inflammation, characterised by leukocyte infiltration and cytokine production, has been implicated in AAA thrombus formation. We studied leukocyte (CD45+) content by flow...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:10.1160/TH12-05-0339

    authors: Sagan A,Mrowiecki W,Mikolajczyk TP,Urbanski K,Siedlinski M,Nosalski R,Korbut R,Guzik TJ

    更新日期:2012-11-01 00:00:00

  • Effect of thrombin on phosphorylation of platelet membrane proteins.

    abstract::The effect of thrombin on the phosphorylating activity of platelet membranes was compared to that of trypsin. Preincubation of non-32P phosphorylated platelet membranes with or without either of these two enzymes resulted in a considerable loss of membrane protein kinase activity which was most severe when trypsin was...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Steiner M

    更新日期:1976-06-30 00:00:00

  • Discrete functional motifs reside within the cytoplasmic tail of alphaV integrin subunit.

    abstract::Previous studies have demonstrated that cell-permeable cytoplasmic tail (CT) alpha(II)beta peptides can modulate the activation of alpha(IIb)b(3). As alpha(V) CT contains an alpha(II)beta homologous region, a series of cell-permeable alpha(V) and alpha(IIb) peptides were generated to determine if alpha(V) CT can modul...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:10.1160/TH07-08-0498

    authors: Haas TA

    更新日期:2008-01-01 00:00:00

  • Inflammation, but not recruitment, of adipose tissue macrophages requires signalling through Mac-1 (CD11b/CD18) in diet-induced obesity (DIO).

    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

    authors: Wolf D,Bukosza N,Engel D,Poggi M,Jehle F,Anto Michel N,Chen YC,Colberg C,Hoppe N,Dufner B,Boon L,Blankenbach H,Hilgendorf I,von Zur Muhlen C,Reinöhl J,Sommer B,Marchini T,Febbraio MA,Weber C,Bode C,Peter K,Lutge

    更新日期:2017-01-26 00:00:00

  • Thrombin generation in rheumatoid arthritis: dependence on plasma factor composition.

    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

    authors: Undas A,Gissel M,Kwasny-Krochin B,Gluszko P,Mann KG,Brummel-Ziedins KE

    更新日期:2010-08-01 00:00:00

  • Procoagulant activity and cytokine expression in whole blood cultures from patients with atherosclerosis supplemented with omega-3 fatty acids.

    abstract::Omega-3 fatty acids (n-3 FA) may reduce atherogenesis and thrombosis. We investigated the effects of n-3 FAs on procoagulant activity and cytokine expression in whole blood cultures from patients with atherosclerosis. Eleven of the 23 included patients had received 5.1 g n-3 FA daily for 6 months (group I) whereas 12 ...

    journal_title:Thrombosis and haemostasis

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:

    authors: Seljeflot I,Johansen O,Arnesen H,Eggesbø JB,Westvik AB,Kierulf P

    更新日期:1999-04-01 00:00:00

  • Phase 2 study of TAK-442, an oral factor Xa inhibitor, in patients following acute coronary syndrome.

    abstract::TAK-442 is an oral direct factor Xa inhibitor. We sought to determine the dose-dependent effect of TAK-442 on major bleeding when added to standard treatment in stabilised patients with acute coronary syndrome (ACS). In this phase II double-blind study, 2,753 ACS patients were randomised to TAK-442 or placebo in addit...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.1160/TH13-07-0543

    authors: Goldstein S,Bates ER,Bhatt DL,Cao C,Holmes D,Kupfer S,Martinez F,Spaeder J,Weitz JI,Ye Z,Zannad F,AXIOM investigators.

    更新日期:2014-06-01 00:00:00

  • Developmental Stage-Specific Manifestations of Absent TPO/c-MPL Signalling in Newborn Mice.

    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

    authors: Lorenz V,Ramsey H,Liu ZJ,Italiano J Jr,Hoffmeister K,Bihorel S,Mager D,Hu Z,Slayton WB,Kile BT,Sola-Visner M,Ferrer-Marin F

    更新日期:2017-12-01 00:00:00

  • Serial determinations of platelet counts in mice by flow cytometry.

    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:

    authors: Alugupalli KR,Michelson AD,Barnard MR,Leong JM

    更新日期:2001-08-01 00:00:00

  • The factor V gene A4070G mutation and the risk of venous thrombosis.

    abstract::The A4070G polymorphism in exon 13 of the factor V (FV) gene, which replaces His by Arg at position 1299 of the B domain, was recently shown to influence circulating FV levels and to contribute to the activated protein C (APC) resistance phenotype. We examined the impact of this polymorphism in a population of unselec...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Alhenc-Gelas M,Nicaud V,Gandrille S,van Dreden P,Amiral J,Aubry ML,Fiessinger JN,Emmerich J,Aiach M

    更新日期:1999-02-01 00:00:00

  • Transcriptional regulation of tissue- and urokinase-type plasminogen activator genes by thrombin in human fetal lung fibroblasts.

    abstract::The mechanism of thrombin induction of tissue- and urokinase-type plasminogen activator (t-PA and u-PA) biosynthesis was investigated in cultured human fetal lung fibroblast cells, IMR-90. Northern blot analysis of total RNA from thrombin-treated cells showed marked accumulations of both t-PA and u-PA mRNA during 24 h...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Hayakawa Y,Tazawa S,Ishikawa T,Niiya K,Sakuragawa N

    更新日期:1995-08-01 00:00:00

  • Extending the pharmacokinetic half-life of coagulation factors by fusion to recombinant albumin.

    abstract::The prophylactic treatment of haemophilia B and the management of haemophilia A or B with inhibitors demand frequent administrations of coagulation factors due to the suboptimal half-lives of the products commercially available and currently in use, e.g. recombinant factor IX (rFIX) and recombinant factor VIIa (rFVIIa...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章,评审

    doi:10.1160/TH13-03-0213

    authors: Metzner HJ,Pipe SW,Weimer T,Schulte S

    更新日期:2013-11-01 00:00:00

  • Changes in von Willebrand factor-cleaving protease (ADAMTS-13) in patients with aortic stenosis undergoing valve replacement or balloon valvuloplasty.

    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

    authors: Bander J,Elmariah S,Aledort LM,Dlott J,Stelzer P,Halperin JL,Kini AS,Sharma SK

    更新日期:2012-07-01 00:00:00

  • Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity. A randomised cross-over trial.

    abstract::The risk of acute cardiovascular events is highest during morning hours, and platelet activity peaks during morning hours. The effect of timing of aspirin intake on circadian rhythm and morning peak of platelet reactivity is not known. It was our objective to evaluate the effect of timing of aspirin intake on circadia...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章,随机对照试验

    doi:10.1160/TH14-05-0453

    authors: Bonten TN,Saris A,van Oostrom MJ,Snoep JD,Rosendaal FR,Zwaginga J,Eikenboom J,van der Meer PF,van der Bom JG

    更新日期:2014-12-01 00:00:00

  • The platelet adhesion capacity to subendothelial matrix and collagen in a flow model during storage of platelet concentrates for 7 days.

    abstract::The influence of storage of platelet concentrates (PC) on the adhesion capacity of platelets was studied. Twenty-four PC, 12 prepared by the buffy coat (BC) method and 12 by the platelet-rich plasma (PRP) method, were stored for 7 days at room temperature. On days 1, 3 and 7 of storage, the platelet adhesion capacity ...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Boomgaard MN,Gouwerok CW,Homburg CH,de Groot G,IJsseldijk MJ,de Korte D

    更新日期:1994-10-01 00:00:00

  • Clot accumulation characteristics of plasminogen-bearing liposomes in a flow-system. Groningen Utrecht Institute for Drug Exploration.

    abstract::In this study, the clot accumulation properties of liposome-coupled plasminogen were compared to those of free (non-liposomal) plasminogen in an in vitro, closed-loop, flow-system. After introduction of a clot into the closed system, double-radiolabelled plasminogen-liposomes were administered and the accumulation of ...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Heeremans JL,Prevost R,Feitsma H,Kluft C,Crommelin DJ

    更新日期:1998-01-01 00:00:00

  • Dysfibrinogenemia (fibrinogen Dusard) associated with impaired fibrin-enhanced plasminogen activation.

    abstract::The fibrin-mediated enhancement of the activation of plasminogen by tissue-type plasminogen activator observed with normal fibrin, is strongly decreased with fibrin Dusard, although the binding of tissue-type plasminogen activator to this fibrin is normal. This impaired fibrin-mediated plasminogen activation is most l...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Lijnen HR,Soria J,Soria C,Collen D,Caen JP

    更新日期:1984-02-28 00:00:00

  • High risk of acquired immune deficiency syndrome (AIDS) and of AIDS related complex (ARC) in hemophiliacs seropositive for more than 5 years.

    abstract::A group of 90 hemophiliacs who had been regularly treated with non virus-inactivated factor VIII or IX concentrates were studied in 1983. At that time 50 patients were HIV-1-antibody positive, 6 additional seroconversions occurred until 1985. 26 of the 50 patients seropositive in 1983 are currently asymptomatic. 4 pat...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Stain C,Pabinger-Fasching I,Guggenberger K,Köller U,Stain M,Hartl H,Heinz F,Mayerhofer S,Kyrle PA,Lechner K

    更新日期:1989-06-30 00:00:00

  • Regulation by nitric oxide of endotoxin-induced tissue factor and plasminogen activator inhibitor-1 in endothelial cells.

    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:

    authors: Pérez-Ruiz A,Montes R,Velasco F,López-Pedrera C,Antonio Páramo J,Orbe J,Hermida J,Rocha E

    更新日期:2002-12-01 00:00:00

  • Participation of Hageman factor dependent pathways in human disease states.

    abstract::Abnormalities of Hageman factor dependent pathways have been described in a wide variety of human disease states. Congenital deficiencies of factor XII (Hageman trait) prekallikrein (Fletcher trait) and high molecular weight kininogen (Williams, Fitzgerald and Flaujeac traits) although resulting in profound in vitro c...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章,评审

    doi:

    authors: Colman RW,Wong PY

    更新日期:1977-12-15 00:00:00

  • Alpha 2-adrenoreceptor status of human platelet subpopulations separated by continuous flow electrophoresis.

    abstract::Human platelets were separated into subpopulations using continuous flow electrophoresis, which uses electrophoretic mobility as the separative parameter. The platelets with the greatest electrophoretic mobility showed higher amounts of total sialic acid than the less electrophoretically mobile subpopulation (74.3 +/-...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Crook M,Crawford N

    更新日期:1993-01-11 00:00:00

  • The inability of propranolol and aspirin to inhibit the response of fibrinolytic activity and factor VIII-antigen to infusion of DDAVP.

    abstract::We tested the response of the fibrinolytic activity and factor VIII-antigen levels to infusion of DDAVP in healthy volunteers and we studied the influence of propranolol and aspirin on this response. After DDAVP, 0.4 microgram/kg in 10 min i.v., the fibrinolytic activity of redissolved euglobulins rose from 179 to 452...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Brommer EJ,Derkx FH,Barrett-Bergshoeff MM,Schalekamp MA

    更新日期:1984-02-28 00:00:00

  • Thrombolytic therapy: overview of results in major vascular occlusions.

    abstract::Thrombolytic therapy provides clinical benefit in patients with vascular occlusions, depending upon the organ or limb that is threatened. The impact of therapeutic intervention varies from the quiet alteration of the course of deep vein thrombosis, for which non-life threatening post-phlebitic syndrome can be largely ...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章,评审

    doi:

    authors: Marder VJ

    更新日期:1995-07-01 00:00:00

  • New functional aspects of the L-arginine-nitric oxide metabolism within the circulating blood.

    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:

    authors: Kleinbongard P,Keymel S,Kelm M

    更新日期:2007-11-01 00:00:00

  • A slow clearing, fibrin-specific, PAI-1 resistant variant of t-PA (T103N, KHRR 296-299 AAAA).

    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:

    authors: Paoni NF,Keyt BA,Refino CJ,Chow AM,Nguyen HV,Berleau LT,Badillo J,Peña LC,Brady K,Wurm FM

    更新日期:1993-08-02 00:00:00

  • Effect of physiological concentrations of vasopressin on components of the fibrinolytic system.

    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:

    authors: Hariman H,Grant PJ,Hughes JR,Booth NA,Davies JA,Prentice CR

    更新日期:1989-04-25 00:00:00

  • Urinary excretion rate of antithrombin III related antigen in cerebral stroke.

    abstract::The urinary excretion rate of antithrombin III related antigen (AT III RA) was examined in cerebral stroke. The excretion rate of AT III RA in cerebral hemorrhage (CH) was 12.33 +/- 1.61 X 10(-4) ml/min. The patients with CH were further classified into two groups: in group CH-I, whose consciousness state was stupor o...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章

    doi:

    authors: Matsuo T,Shinomiya K,Okuno S,Matsuo C,Matsuo O

    更新日期:1984-12-29 00:00:00

  • Acquired factor XIII deficiency: a therapeutic challenge.

    abstract::Less than 60 cases of acquired factor (F)XIII deficiencies have been reported, most having distinct clinical features. To illustrate the therapeutic challenges of acquired FXIII inhibitors, we report a case of a 65-year-old patient with no previous bleeding history who suddenly developed massive haemorrhages associate...

    journal_title:Thrombosis and haemostasis

    pub_type: 杂志文章,评审

    doi:10.1160/TH12-08-0604

    authors: Boehlen F,Casini A,Chizzolini C,Mansouri B,Kohler HP,Schroeder V,Reber G,de Moerloose P

    更新日期:2013-03-01 00:00:00