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Thrombosis & Haemostasis
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  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0340-6245 - ISSN (Online) 2567-689X
Published by Thieme Publishing Group Homepage  [238 journals]
  • Gender Specificity and Interpretation of Functional Cardiac Imaging: Let's
           Talk about Sex
    • Thromb Haemost 2019; 119: 1379-1381
      DOI: 10.1055/s-0039-1695010



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 119: 1379-13812019-09-01T00:00:00+01:00
      Issue No: Vol. 119, No. 09 (2019)
       
  • Hematopoietic Stem Cell Transplantation-Associated Thrombotic
           Microangiopathy: Pathophysiology and Differentiation from Graft versus
           Host Disease
    • Thromb Haemost 2019; 119: 1382-1382
      DOI: 10.1055/s-0039-1695731



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 119: 1382-13822019-09-01T00:00:00+01:00
      Issue No: Vol. 119, No. 09 (2019)
       
  • FVIIa Neutralization by a FXa Inhibitor: How It Could Dampen Tumorigenic
           Cancer Cell Phenotypes
    • Thromb Haemost 2019; 119: 1383-1383
      DOI: 10.1055/s-0039-1695732



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 119: 1383-13832019-09-01T00:00:00+01:00
      Issue No: Vol. 119, No. 09 (2019)
       
  • Next-Generation Therapeutic Concepts for Atherosclerosis: Focus on Cell
           Specificity and Noncoding RNAs
    • Thromb Haemost 2019; 119: 1199-1201
      DOI: 10.1055/s-0039-1693412



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 119: 1199-12012019-08-02T00:00:00+01:00
      Issue No: Vol. 119, No. 08 (2019)
       
  • Using Context-Sensitive Text Mining to Identify miRNAs in Different Stages
           of Atherosclerosis
    • Authors: Joppich; Markus, Weber, Christian, Zimmer, Ralf
      Pages: 1247 - 1264
      Abstract: 790 human and mouse micro-RNAs (miRNAs) are involved in diseases. More than 26,428 miRNA–gene interactions are annotated in humans and mice. Most of these interactions are posttranscriptional regulations: miRNAs bind to the messenger RNAs (mRNAs) of genes and induce their degradation, thereby reducing the gene expression of target genes. For atherosclerosis, 667 miRNA–gene interactions for 124 miRNAs and 343 genes have been identified and described in numerous publications. Some interactions were observed through high-throughput experiments, others were predicted using bioinformatic methods, and some were determined by targeted experiments. Several reviews collect knowledge on miRNA–gene interactions in (specific aspects of) atherosclerosis.Here, we use our bioinformatics resource (atheMir) to give an overview of miRNA–gene interactions in the context of atherosclerosis. The interactions are based on public databases and context-based text mining of 28 million PubMed abstracts. The miRNA–gene interactions are obtained from more than 10,000 publications, of which more than 1,000 are in a cardiovascular disease context (266 in atherosclerosis). We discuss interesting miRNA–gene interactions in atherosclerosis, grouped by specific processes in different cell types and six phases of atherosclerotic progression. All evidence is referenced and easily accessible: Relevant interactions are provided by atheMir as supplementary tables for further evaluation and, for example, for the subsequent data analysis of high-throughput measurements as well as for the generation and validation of hypotheses. The atheMir approach has several advantages: (1) the evidence is easily accessible, (2) regulatory interactions are uniformly available for subsequent high-throughput data analysis, and (3) the resource can incrementally be updated with new findings.
      Citation: Thromb Haemost 2019; 119: 1247-1264
      PubDate: 2019-08-02T00:00:00+01:00
      DOI: 10.1055/s-0039-1693165
      Issue No: Vol. 119, No. 08 (2019)
       
  • Lysophosphatidylcholine is a Major Component of Platelet Microvesicles
           Promoting Platelet Activation and Reporting Atherosclerotic Plaque
           Instability
    • Authors: Diehl; Philipp, Nienaber, Frederik, Zaldivia, Maria T. K., Stamm, Johannes, Siegel, Patrick M., Mellett, Natalie A., Wessinger, Marius, Wang, Xiaowei, McFadyen, James D., Bassler, Nicole, Puetz, Gerhard, Htun, Nay M., Braig, David, Habersberger, Jonathon, Helbing, Thomas, Eisenhardt, Steffen U., Fuller, Maria, Bode, Christoph, Meikle, Peter J., Chen, Yung Chih, Peter, Karlheinz
      Pages: 1295 - 1310
      Abstract: Background Microvesicles (MVs) are small cell-derived vesicles, which are mainly released by activated cells. They are part of a communication network delivering biomolecules, for example, inflammatory molecules, via the blood circulation to remote cells in the body. Platelet-derived MVs are known to induce vascular inflammation. Research on the mediators and mechanisms of their inflammatory effects has attracted major interest. We hypothesize that specific lipids are the mediators of vascular inflammation caused by platelet-derived MVs. Methods and Results Liquid chromatography electrospray ionization–tandem mass spectrometry was used for lipid profiling of platelet-derived MVs. Lysophosphatidylcholine (LPC) was found to be a major component of platelet-derived MVs. Investigating the direct effects of LPC, we found that it induces platelet activation, spreading, migration and aggregation as well as formation of inflammatory platelet–monocyte aggregates. We show for the first time that platelets express the LPC receptor G2AR, which mediates LPC-induced platelet activation. In a mouse model of atherosclerotic plaque instability/rupture, circulating LPC was detected as a surrogate marker of plaque instability. These findings were confirmed by matrix-assisted laser desorption ionization imaging, which showed that the LPC concentration of human plaques was highest in vulnerable plaque regions. Conclusion LPC is a major component of platelet-derived MVs and via its interaction with G2AR on platelets contributes to platelet activation, spreading, migration and aggregation and ultimately to vascular inflammation. Circulating LPC reports on atherosclerotic plaque instability in mice and is significantly increased in unstable areas of atherosclerotic plaques in both mice and humans, linking LPC to plaque instability.
      Citation: Thromb Haemost 2019; 119: 1295-1310
      PubDate: 2019-08-02T00:00:00+01:00
      DOI: 10.1055/s-0039-1683409
      Issue No: Vol. 119, No. 08 (2019)
       
  • The Use of Biomarkers in Clinical Management Guidelines: A Critical
           Appraisal
    • Authors: Esteve-Pastor; María Asunción, Roldán, Vanessa, Rivera-Caravaca, José Miguel, Ramírez-Macías, Inmaculada, Lip, Gregory Y. H., Marín, Francisco
      Abstract: In cardiovascular disease (CVD), biomarkers (i.e., “biological markers”) could have multiple roles in understanding the complexity of cardiovascular (CV) pathophysiology and to offer an integrated approach to management. Biomarkers could help in daily practice as a diagnostic tool, to monitor therapy response, to assess prognosis and as early marker of CV damage, or to stratify risk. In recent years, the role of biomarkers in CVD is even more relevant and some have recently been included in clinical management guideline recommendations. The aim of this review is to discuss the recommendations in clinical guidelines of various biomarkers and to review their usefulness in daily clinical practice. Ultimately, a balance is needed between simplicity and practicality for clinical decision-making. Most biomarkers (whether blood, urine, or imaging-based) will improve on clinical risk stratification, but awaiting biomarker results may lead to delays in the initiation of therapy, for example, anticoagulation for stroke prevention in atrial fibrillation. Many biomarkers are nonspecific, being predictive of many CV and non-CV outcomes, so would be better as “rule-out” rather than “rule-in” assessments. Derivation of some biomarkers have also been made in highly selected clinical trial cohorts, where measurement is made at baseline but outcomes determined many years later; given the dynamic nature of risk in the “real world” where patients get older and develop incident risk factors, this may give a false impression of the risk profile. Finally, some laboratory biomarkers have a diurnal variation and inter-/intravariability (and lower limits of detection) in assays, which may be expensive, are added considerations.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-09-09T00:00:00+01:00
      DOI: 10.1055/s-0039-1696955
       
  • Tie2 Activation Promotes Protection and Reconstitution of the Endothelial
           Glycocalyx in Human Sepsis
    • Authors: Drost; Carolin Christina, Rovas, Alexandros, Kusche-Vihrog, Kristina, Van Slyke, Paul, Kim, Harold, Hoang, Van C, Maynes, Jason T., Wennmann, Dirk Oliver, Pavenstädt, Hermann, Linke, Wolfgang, Lukasz, Alexander, Hesse, Bettina, Kümpers, Philipp
      Abstract: The endothelial glycocalyx (eGC), a carbohydrate-rich layer lining the luminal surface of the endothelium, provides a first vasoprotective barrier against vascular leakage in sepsis. We hypothesized that angiopoietin-2 (Angpt-2), antagonist of the endothelium-stabilizing receptor Tie2, induces a rapid loss of the eGC in human sepsis. Using intravital microscopy, we measured the perfused boundary region (PBR), an inverse parameter of eGC dimensions in sublingual microvessels, in patients with sepsis and age-matched nonseptic subjects. Median PBR values were significantly higher in patients compared with controls and correlated with serum Angpt-2 levels. To transfer and further explore these findings in a cell culture system, we exposed endothelial cells (ECs) to serum (5%) from a subgroup of septic patients and nonseptic controls. Confocal and atomic force microscopy revealed that sepsis serum, but not control serum, induced thinning of the eGC on human ECs in vitro, which correlated with paired PBR values obtained in vivo (r = 0.96, p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-09-07T00:00:00+01:00
      DOI: 10.1055/s-0039-1695768
       
  • ABT-737 Triggers Caspase-Dependent Inhibition of Platelet Procoagulant
           Extracellular Vesicle Release during Apoptosis and Secondary Necrosis In
           Vitro
    • Authors: Wei; Hao, Harper, Matthew T.
      Abstract: Platelet lifespan is limited by activation of intrinsic apoptosis. Apoptotic platelets are rapidly cleared from the circulation in vivo. ABT-737 triggers platelet apoptosis and is a useful tool for studying this process. However, in vitro experiments lack clearance mechanisms for apoptotic platelets. To determine whether apoptotic platelets progress to secondary necrosis, apoptosis was triggered in human platelets with ABT-737, a BH3 mimetic. Platelet annexin V (AnV) binding, release of AnV+ extracellular vesicles (EVs), and loss of plasma membrane integrity were monitored by flow cytometry. ABT-737 triggered AnV binding, indicating phosphatidylserine exposure, release of AnV+ EVs, and a slow loss of plasma membrane integrity. The latter suggests that apoptotic platelets progress to secondary necrosis in vitro. These responses were dependent on caspase activation and Ca2+ entry. Surprisingly, although intracellular Ca2+ concentration increased, AnV+ EV release was not dependent on the Ca2+-dependent protease, calpain. On the contrary, ABT-737 downregulated the ability of the Ca2+ ionophore, A23187, to trigger calpain-dependent release of AnV+ EVs. This was dependent on caspase activity as, when caspases were inhibited, ABT-737 increased the ability of A23187 to trigger AnV+ EV release. These data suggest that apoptotic platelets progress to secondary necrosis unless they are cleared. This may affect the interpretation of ABT-737-triggered signaling in platelets in vitro. Ca2+-dependent AnV+ EV release is downregulated during apoptosis in a caspase-dependent manner, which may limit the potential consequences of secondary necrotic platelets.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-09-07T00:00:00+01:00
      DOI: 10.1055/s-0039-1693694
       
  • Apolipoprotein B100/Low-Density Lipoprotein Regulates Proteolysis and
           Functions of von Willebrand Factor under Arterial Shear
    • Authors: Cao; Wenjing, Abdelgawwad, Mohammad S., Li, Jingzhi, Zheng, X. Long
      Abstract: Background Proteolytic cleavage of von Willebrand factor (VWF) by a plasma a disintegrin and metalloproteinase with a thrombospondin type 1 motifs, member 13 (ADAMTS13) is regulated by shear stress and binding of coagulation factor VIII, platelets or platelet glycoprotein 1b, and ristocetin to VWF. Objective Current study aims to identify novel VWF binding partners that may modulate VWF functions under physiological conditions. Methods A deoxyribonucleic acid aptamer-based affinity purification of VWF, followed by tandem mass spectrometry, functional, and binding assays was employed. Results Apolipoprotein B100/low-density lipoprotein (apoB100/LDL) was identified as a novel VWF-binding partner. Purified apoB100/LDL was able to accelerate the proteolytic cleavage of VWF by ADAMTS13 under shear in a concentration-dependent manner. This rate-enhancing activity was dramatically reduced when apoB100/LDL was oxidized. More interestingly, the oxidized apoB100/LDL appeared to compete with native apoB100/LDL for its enhancing activity on VWF proteolysis under shear. As a control, a purified apoA1/high-density lipoprotein (apoA1/HDL) or apoB48 exhibited a minimal or no activity enhancing VWF proteolysis by ADAMTS13 under the same conditions. Both VWF and ADAMTS13 were able to bind native or oxidized apoB100/LDL with high affinities. No binding interaction was detected between VWF (or ADAMTS13) and apoA1/HDL (or apoB48). Moreover, apoB100/LDL but not its oxidized products inhibited the adhesion of platelets to ultra large VWF released from endothelial cells under flow. Finally, significantly reduced ratios of high to low molecular weight of VWF multimers with increased levels of plasma VWF antigen were detected in LDLR−/− mice fed with high cholesterol diet. Conclusion These results indicate that apoB100/LDL may be a novel physiological regulator for ADAMTS13-VWF functions.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-09-07T00:00:00+01:00
      DOI: 10.1055/s-0039-1696713
       
  • Single Low Dose of rFVIIa Combined with Antifibrinolytic Agent is a Simple
           and Safe Treatment for Factor XI-Deficient Patients undergoing Surgery
    • Authors: Salomon; Ophira, Budnik, Ivan, Avishai, Einat, Tamarin, Ilia, Bashari, Dalia, Dardik, Rima, Livnat, Tami
      Abstract: Background Factor XI (FXI) deficiency is a rare autosomal bleeding disorder. The rarity of spontaneous bleeding and absence of optimal tools to predict the bleeding risk in FXI-deficient patients hamper the standardization of prophylactic treatment enabling them to undergo major surgeries without blood products. Objectives We explored the effectiveness of a single and very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid (TXA) as prophylactic treatment for FXI-deficient patients undergoing various types of surgery at various sites of injury. We studied the potential use of thrombin generation (TG) as a surrogate tool for predicting thrombogenicity. Patients and Methods Our cohort consisted of 10 patients with severe FXI deficiency undergoing 12 interventions. Patients received a single dose of 10 to 15 μg/kg rFVIIa at the end of surgery in addition to TXA initiated 2 hours before surgery at the dose of 4 g/day for 3 to 5 days. TG was tested before and 30 minutes after rFVIIa administration. Results All operations were uneventful and none of the patients bled excessively or required blood products. No thrombotic event was reported, and the postoperative hospitalization duration was comparable to that of patients without bleeding disorders. TG performed at the peak of rFVIIa was below the curve of healthy controls, thus confirming that the administered dose was not thrombogenic. Conclusion A single very low dose of rFVIIa along with TXA is a simple and safe treatment to control hemostasis in severe FXI-deficient patients undergoing diverse type of surgical procedure at various sites.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-09-07T00:00:00+01:00
      DOI: 10.1055/s-0039-1696685
       
  • Magnetic Targeting Improves the Therapeutic Efficacy of
           Microbubble-Mediated Obstructive Thrombus Sonothrombolysis
    • Authors: Chen; Xiaoqiang, Wu, Weilan, Wang, Shifei, Zhong, Jiayuan, Djama, Nima Moumin, Wei, Guoquan, Lai, Yanxian, Si, Xiaoyun, Cao, Shiping, Liao, Wangjun, Liao, Yulin, Li, Hairui, Bin, Jianping
      Abstract: Background Magnetic targeting may help microbubbles (MBs) reach obstructive thrombi and improve the efficacy of MB-mediated sonothrombolysis, but the role of magnetic targeting in MB-mediated sonothrombolysis remains elusive. Objectives We investigate the feasibility and efficacy of magnetically targeted MB-mediated sonothrombolysis for the treatment of obstructive thrombi. Materials and Methods Red and white thromboembolic models were established in vitro and in vivo. The models were randomly assigned to the control, ultrasound plus control MB (US + C-MB), ultrasound plus magnetic MB (US + M-MB), or US + M-MB + recombinant tissue-type plasminogen activator (r-tPA) groups and treated for 30 minutes. The recanalization rate, average blood flow velocity, hindlimb perfusion, and skeletal muscle injury marker levels were recorded. Results The recanalization rate, average blood flow velocity, and hindlimb perfusion in the red and white thromboembolic models were all significantly higher in the US + M-MB and US + M-MB + r-tPA groups than in the control and US + C-MB groups both in vitro and in vivo. Moreover, the levels of the skeletal muscle injury markers were all significantly lower in the US + M-MB and US + M-MB + r-tPA groups than in the other two groups in vivo for both thromboembolic models. However, the thrombolytic effects of red thrombi performed better than those of white thrombi in the US + M-MB + r-tPA group. Conclusion M-MB-mediated sonothrombolysis improves the efficacy of thrombolysis both in vitro and in vivo, and reduces tissue damage in clogging model; thus, this method may serve as a promising approach for treating thrombus-occlusive diseases.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-09-02T00:00:00+01:00
      DOI: 10.1055/s-0039-1695767
       
  • Transcriptome Analysis of Reticulated Platelets Reveals a Prothrombotic
           Profile
    • Authors: Bongiovanni; Dario, Santamaria, Gianluca, Klug, Melissa, Santovito, Donato, Felicetta, Arianna, Hristov, Michael, von Scheidt, Moritz, Aslani, Maria, Cibella, Javier, Weber, Christian, Moretti, Alessandra, Laugwitz, Karl-Ludwig, Peano, Clelia, Bernlochner, Isabell
      Abstract: Reticulated platelets (RPs) are larger, hyperreactive platelets that contain significantly more ribonucleic acid (RNA) compared with mature platelets (MPs). High levels of RPs in peripheral blood are predictors of an insufficient response to dual antiplatelet therapy in cardiovascular patients and of adverse cardiovascular events. However, the mechanisms underlying these correlations remain widely unknown and the biology of RPs has not been investigated yet. Here, we compared for the first time the transcriptomic profiles of RPs and MPs isolated from peripheral blood of healthy donors. Total RNA sequencing revealed 1,744 differentially expressed genes (670 downregulated, 1,074 upregulated) in RPs compared with MPs. In particular, transcripts for the collagen receptor GP6, thromboxane receptor A2 (TBXA2R), thrombin receptor PAR4 (F2RL3), and adenosine triphosphate receptors P2RX1, ORAI2, and STIM1 (both involved in calcium signaling) were significantly upregulated in RPs, whereas several RNA regulators as the ribonuclease PARN, the RISC-component TNRC6A, and the splicing factor LUC7L3 were downregulated in RPs. Gene ontology analysis revealed an enrichment of relevant biological categories in RPs including platelet activation and blood coagulation. Gene Set Enrichment Analysis showed an overrepresentation of several platelet activation pathways like thrombin, thromboxane, and glycoprotein IIb/IIIa signaling in RPs. Small-RNA sequencing reported 9 micro-RNAs significantly downregulated in RPs with targets involved in platelet reactivity. Our data show for the first time an enrichment of several prothrombotic transcripts in RPs providing a first biological explanation for their hyperreactive phenotype.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-09-01T00:00:00+01:00
      DOI: 10.1055/s-0039-1695009
       
  • Effects of Edoxaban on the Cellular and Protein Phase of Coagulation in
           Patients with Coronary Artery Disease on Dual Antiplatelet Therapy with
           Aspirin and Clopidogrel: Results of the EDOX-APT Study
    • Authors: Franchi; Francesco, Rollini, Fabiana, Garcia, Emilio, Rivas Rios, Jose, Rivas, Andrea, Agarwal, Malhar, Kureti, Megha, Nagaraju, Deepa, Wali, Mustafa, Briceno, Maryuri, Moon, Jae Youn, Kairouz, Victor, Yaranov, Dmitry, Been, Latonya, Suryadevara, Siva, Soffer, Daniel, Zenni, Martin M., Bass, Theodore A., Angiolillo, Dominick J.
      Abstract: In patients requiring dual antiplatelet therapy (DAPT) who also have an indication to be treated with oral anticoagulant (OAC) drugs, aspirin withdrawal reduces the risk of bleeding. There is limited data on the pharmacodynamic effects associated with adding a nonvitamin K antagonist OAC on a background of aspirin and a P2Y12 inhibitor as well as dropping aspirin. Seventy-five patients on DAPT (aspirin plus clopidogrel) were randomized to DAPT plus high-dose edoxaban (60 mg once daily, Group A), DAPT plus low-dose edoxaban (30 mg once daily, Group B), or DAPT only (Group C) for 10 ± 2 days (Phase I). Afterwards, Groups A and B interrupted aspirin and maintained clopidogrel plus edoxaban for 10 ± 2 days, while patients in Group C maintained DAPT (Phase II). Platelet aggregation and clot kinetics were assessed at baseline, end of Phase I, and end of Phase II using thrombelastography (TEG), light transmittance aggregometry (LTA), VerifyNow P2Y12, and serum thromboxane-B2. The primary endpoint was the comparison of maximum amplitude (MA) measured by TEG, a measure of clot strength, between patients on DAPT plus high-dose edoxaban and patients on DAPT only. Edoxaban prolonged in a dose-dependent manner speed of thrombin generation (TEG R; Group A: 7.7 [6.8–8.7] vs. Group B: 7.4 [6.4–8.5] vs. Group C: 6.3 [5.7–7.0]; p = 0.05) but did not affect other markers of clot kinetics, including TEG MA (Group A: 63 [61–64] vs. Group B: 65 [63–67] vs. Group C: 64 [63–65]; p = 0.10). After aspirin discontinuation, platelet reactivity assessed by LTA using thrombin receptor activating peptide as agonist increased to a greater extent with low-dose edoxaban. Stopping aspirin did not affect markers of P2Y12 reactivity and had no or marginal effects on clot kinetics, but increased markers sensitive to cyclooxygenase-1 blockade.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-30T00:00:00+01:00
      DOI: 10.1055/s-0039-1695772
       
  • Global Use of Idarucizumab in Clinical Practice: Outcomes of the RE-VECTO
           Surveillance Program
    • Authors: Fanikos; John, Murwin, Debra, Gruenenfelder, Fredrik, Tartakovsky, Igor, França, Lionel Riou, Reilly, Paul A., Kermer, Pawel, Wowern, Frederik von, Lane, Deirdre A., Butcher, Ken
      Abstract: Idarucizumab was approved for the reversal of dabigatran in 2015. We investigated whether postapproval usage patterns of idarucizumab in a real-world setting reflect those observed in the pivotal trials. No safety or efficacy data were collected in this medical record-based observational study. RE-VECTO, a global postapproval, international, surveillance program, involved hospital pharmacies in countries where idarucizumab was licensed and dispensed (August 2016–June 2018). Characteristics of sites prescribing idarucizumab and of eligible patients (≥ 18 years old and receiving idarucizumab regardless of prior oral anticoagulant use), as well as idarucizumab utilization data, were collected and analyzed descriptively. Sixty-one sites enrolled 359 patients. Most pharmacies (85.2%) were centralized, and the median idarucizumab units stocked per hospital was 2.0 (interquartile range, 1.0–3.0). Almost three-quarters of patients were elderly (74.9% aged > 70 years), and only four (1.1%) had received idarucizumab before. Nearly all patients were treated with dabigatran (97.5%). There was a low frequency of unapproved dabigatran dosage regimens (3.3%). Life-threatening or uncontrolled bleeding was the most frequent indication for idarucizumab (57.7%), followed by emergency surgery/urgent procedure (35.9%). Of the life-threatening bleeding events, the most frequent were gastrointestinal tract (44.4%) and intracranial (38.6%). Most patients (95.0%) were given the full dose of two vials (2 × 2.5 g) of idarucizumab initially, and very few (1.7%) received a second dose. Of those patients requiring emergency or scheduled/planned surgery/procedures, 25.5% underwent gastrointestinal and/or abdominal surgery/procedures. Real-world usage patterns of idarucizumab provide valuable insights into emergency reversal strategies. Off-label use was minimal.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-30T00:00:00+01:00
      DOI: 10.1055/s-0039-1695771
       
  • Idarucizumab for Reversion of Anticoagulant Effect in Daily Practice
    • Thromb Haemost
      DOI: 10.1055/s-0039-1696646



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost ; : -2019-08-30T00:00:00+01:00
       
  • Understanding the Effects of NOAC Combined with Antiplatelet Therapy on
           Clot Kinetics
    • Thromb Haemost
      DOI: 10.1055/s-0039-1696645



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost ; : -2019-08-30T00:00:00+01:00
       
  • Fibrin-VLDL Receptor-Dependent Pathway Promotes Leukocyte Transmigration
           by Inhibiting Src Kinase Fyn and is a Target for Fibrin β15-42 Peptide
    • Authors: Yakovlev; Sergiy, Cao, Chunzhang, Galisteo, Rebeca, Zhang, Li, Strickland, Dudley K., Medved, Leonid
      Abstract: According to the current view, binding of fibrin degradation product E1 fragment to endothelial VE-cadherin promotes transendothelial migration of leukocytes and thereby inflammation, and fibrin-derived β15–42 peptide reduces leukocyte transmigration by competing with E1 for binding to VE-cadherin and, in addition, by signaling through Src kinase Fyn. However, the very low affinity of β15–42 to VE-cadherin raised a question about its ability to inhibit E1–VE-cadherin interaction. Further, our previous study revealed that fibrin promotes leukocyte transmigration through the very-low-density lipoprotein (VLDL) receptor (VLDLR)-dependent pathway and suggested a possible link between the inhibitory properties of β15–42 and this pathway. To test such a link and the proposed inhibitory mechanisms for β15–42, we performed in vitro experiments using surface plasmon resonance, enzyme-linked immunosorbent assay, and leukocyte transendothelial migration assay, and in vivo studies with wild-type and VLDLR-deficient mice using mouse model of peritonitis. The experiments revealed that β15–42 cannot inhibit E1–VE-cadherin interaction at the concentrations used in the previous in vivo studies leaving the proposed Fyn-dependent signaling mechanism as a viable explanation for the inhibitory effect of β15–42. While testing this mechanism, we confirmed that Fyn plays a critical role in controlling fibrin-induced transendothelial migration of leukocytes and found that signaling through the VLDLR-dependent pathway results in inhibition of Fyn, thereby increasing leukocyte transmigration. Furthermore, our in vivo experiments revealed that β15–42 inhibits this pathway, thereby preventing inhibition of Fyn and reducing leukocyte transmigration. Thus, this study clarifies the molecular mechanism underlying the VLDLR-dependent pathway of leukocyte transmigration and reveals that this pathway is a target for β15–42.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-29T00:00:00+01:00
      DOI: 10.1055/s-0039-1695008
       
  • Multistate Models: Accurate and Dynamic Methods to Improve Predictions of
           Thrombotic Risk in Patients with Cancer
    • Authors: Carmona-Bayonas; Alberto, Jimenez-Fonseca, Paula, Garrido, Marcelo, Custodio, Ana, Hernandez, Raquel, Lacalle, Alejandra, Cano, Juana María, Aguado, Gema, Martínez de Castro, Eva, Alvarez Manceñido, Felipe, Macias, Ismael, Visa, Laura, Martín Richard, Marta, Mangas, Monserrat, Sánchez Cánovas, Manuel, Longo, Federico, Iglesias Rey, Leticia, Martínez Lago, Nieves, Martín Carnicero, Alfonso, Sánchez, Ana, Azkárate, Aitor, Limón, María Luisa, Hernández Pérez, Carolina, Ramchandani, Avinash, Pimentel, Paola, Cerdá, Paula, Serrano, Raquel, Gil-Negrete, Aitziber, Marín, Miguel, Hurtado, Alicia, Sánchez Bayona, Rodrigo, Gallego, Javier
      Abstract: Research into cancer-associated thrombosis (CAT) entails managing dynamic data that pose an analytical challenge. Thus, methods that assume proportional hazards to investigate prognosis entail a risk of misinterpreting or overlooking key traits or time-varying effects. We examined the AGAMENON registry, which collects data from 2,129 patients with advanced gastric cancer. An accelerated failure time (AFT) multistate model and flexible competing risks regression were used to scrutinize the time-varying effect of CAT, as well as to estimate how covariates dynamically predict cumulative incidence. The AFT model revealed that thrombosis shortened progression-free survival and overall survival with adjusted time ratios of 0.72 and 0.56, respectively. Nevertheless, its prognostic effect was nonproportional and disappeared over time if the subject managed to survive long enough. CAT that occurred later had a more pronounced prognostic effect. In the flexible competing risks model, multiple covariates were seen to have significant time-varying effects on the cumulative incidence of CAT (Khorana score, secondary thromboprophylaxis, high tumor burden, and cisplatin-containing regimen), whereas other predictors exerted a constant effect (signet ring cells and primary thromboprophylaxis). The model that assumes proportional hazards was incapable of capturing the effect of these covariates and predicted the cumulative incidence in a biased way. This study evinces that flexible and multistate models are a useful and innovative method to describe the dynamic effect of variables associated with CAT and should be more widely used.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-28T00:00:00+01:00
      DOI: 10.1055/s-0039-1694012
       
  • Relationship of Platelet Reactivity and Inflammatory Markers to Recurrent
           Adverse Events in Patients with ST-Elevation Myocardial Infarction
    • Authors: Adatia; Krishma, Farag, Mohamed F., Gue, Ying X., Srinivasan, Manivannan, Gorog, Diana A.
      Abstract: Background Patients with ST-elevation myocardial infarction (STEMI) exhibit pro-thrombotic and pro-inflammatory states. Markers of enhanced platelet reactivity and inflammation are predictive of adverse outcome. However, the relationship between these biomarkers, and their combined usefulness for risk stratification, is not clear. Methods In a prospective study of 541 patients presenting with STEMI, blood samples were taken on arrival to measure high-sensitivity C-reactive protein (hs-CRP), neutrophil/lymphocyte ratio (NLR) and platelet reactivity using the point-of-care Global Thrombosis Test. These biomarkers, alone and in combination, were related to the occurrence of major adverse cardiovascular events (MACE, defined as composite of cardiovascular death, myocardial infarction and cerebrovascular accident) at 30 days and 12 months. Results Platelet reactivity and hs-CRP, but not NLR, were weakly predictive of MACE at 30 days and 12 months. The combination of enhanced platelet reactivity and raised hs-CRP was strongly predictive of MACE at 30 days (hazard ratio [HR] 3.46 [95% confidence interval [CI] 1.81–6.62], p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-22T00:00:00+01:00
      DOI: 10.1055/s-0039-1695007
       
  • Decoration of Fibrin with Extracellular Chaperones
    • Authors: Talens; Simone, Leebeek, Frank W. G., Veerhuis, Robert, Rijken, Dingeman C.
      Abstract: Background Many proteins bind to fibrin during clot formation in plasma. We previously identified by mass spectrometry the most abundant proteins that noncovalently bind to fibrin clots. Several of these proteins (e.g., apolipoprotein J/clusterin, haptoglobin, α2-macroglobulin, α1-antitrypsin) can act as extracellular chaperones. Objective We hypothesize that clot-binding proteins may interact with fibrin as chaperones. The goal of this study is to test this hypothesis and to investigate the origin of the cross-β or amyloid structures in fibrin clots, which are associated with protein unfolding. Methods and Results A thioflavin T assay was used to detect cross-β structures. A steadily increasing amount was measured in the fibrinogen fraction of plasma during heat stress, a standard treatment to induce unfolding of proteins. Heat-stressed plasma was clotted and clot-bound proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The results showed that the amounts of the clot-bound proteins were related to the duration of the heat stress. This indicates that cross-β structures in unfolded fibrin(ogen) are involved in clot binding of the proteins, which supports our chaperone hypothesis. A contributing role of fibrin formation itself was studied by clotting purified fibrinogen with thrombin in the presence of thioflavin T. The fluorescence intensity increased in time in the presence of thrombin, but did not increase in its absence. This provides evidence for the generation of cross-β structures during fibrin formation. Conclusion Fibrin clots generated in plasma are decorated with extracellular chaperones. The binding of these chaperones involves cross-β structures originating both from unfolded fibrinogen and from fibrin formation.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-22T00:00:00+01:00
      DOI: 10.1055/s-0039-1693701
       
  • Platelet Indices and Risk of Death and Cardiovascular Events: Results from
           a Large Population-Based Cohort Study
    • Authors: Patti; Giuseppe, Di Martino, Giuseppe, Ricci, Fabrizio, Renda, Giulia, Gallina, Sabina, Hamrefors, Viktor, Melander, Olle, Sutton, Richard, Engström, Gunnar, De Caterina, Raffaele, Fedorowski, Artur
      Abstract: Studies evaluating the relationship between platelet indices and cardiovascular (CV) outcomes yielded conflicting results. We assessed the incidence of adverse events according to baseline quintiles of platelet indices in the prospective cohort of the Malmö Diet and Cancer Study. A total of 30,314 individuals (age 57 ± 8 years) were followed for a median of 16 years (468,490 person-years). Outcome measures included all-cause death, CV death, myocardial infarction (MI), and ischemic stroke. The fifth quintile of platelet count (> 274.6 × 109/L) was associated with higher incidence of all-cause death (hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.09–1.32, p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-20T00:00:00+01:00
      DOI: 10.1055/s-0039-1694969
       
  • Use of Prophylaxis for Prevention of Venous Thromboembolism in Patients
           with Isolated Foot or Ankle Surgery: A Systematic Review and Meta-Analysis
           
    • Authors: Bikdeli; Bavand, Visvanathan, Renuka, Jimenez, David, Monreal, Manuel, Goldhaber, Samuel Z., Bikdeli, Behnood
      Abstract: Although prophylaxis for venous thromboembolism (VTE) is recommended after many surgeries, evidence base for use of VTE prophylaxis after foot or ankle surgery has been elusive, leading into varying guidelines recommendations and notable practice variations. We conducted a systematic review of the literature to determine if use of VTE prophylaxis decreased the frequency of subsequent VTE, including deep vein thrombosis (DVT) or pulmonary embolism (PE), compared with control. We searched PubMed, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov through May 2018, for randomized controlled trials (RCTs) or prospective controlled observational studies of VTE prophylaxis in patients undergoing foot and ankle surgery. Our search retrieved 263 studies, of which 6 were finally included comprising 1,600 patients. Patients receiving VTE prophylaxis had lower risk for subsequent DVT (risk ratio [RR]: 0.72; 95% confidence interval [CI]: 0.55–0.94) and subsequent VTE (RR: 0.72; 95% CI: 0.55–0.94). There was only one case of nonfatal PE, no cases of fatal PE, and no change in all-cause mortality (RR: 3.51; 95% CI: 0.14–84.84). There was no significant difference in the risk for bleeding (RR: 2.12; 95% CI: 0.53–8.56). Very few RCTs exist regarding the efficacy and safety of VTE prophylaxis in foot and ankle surgery. Prophylaxis appears to reduce the risk of subsequent VTE, but the event rates are low and symptomatic events are rare. Future studies should determine the subgroups of patients undergoing foot or ankle surgery in whom prophylaxis may be most useful.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-20T00:00:00+01:00
      DOI: 10.1055/s-0039-1693464
       
  • Aspirin and Primary Prevention in Patients with Diabetes—A Critical
           Evaluation of Available Randomized Trials and Meta-Analyses
    • Authors: Schrör; Karsten, Kristensen, Steen D., Storey, Robert F., Verheugt, Freek W. A.
      Abstract: Primary prevention of cardiovascular events with aspirin in patients with elevated cardiovascular risk, including diabetics, is currently under intense discussion. Data from meta-analyses suggests that the efficacy of aspirin in these patients is low, whereas there is a significantly increased bleeding tendency. However, meta-analyses are based on trials that differ in many important aspects, including study selection. Fresh insights were expected from the ASCEND trial, by far the largest primary, randomized, placebo-controlled prevention trial in diabetics without known cardiovascular disease. There was a small but significant reduction in serious cardiovascular events by aspirin (8.6% vs. 9.6%) but also a significant increase in major bleeding: 4.1% versus 3.2%. Unfortunately, this trial did not meet the desired annual rate of elevated vascular risk of ≥ 2%. It was only 1.2 to 1.3%, and thus in the range of other primary prevention trials in low-risk patients. Apart from potential compliance problems, possible explanations for the small cardioprotective effect of antiplatelet treatment include a healthy lifestyle as well as improved vascular protection by comedication with vasoactive and anti-inflammatory drugs, such as statins or antihypertensive agents, as well as proton-pump inhibitors that might modify bleeding, specifically in the upper gastrointestinal tract—the most frequently affected site. Also, the introduction of new antidiabetic drugs with more favorable cardiovascular effects may in part explain the low event rate. ASCEND, similar to ARRIVE, did not study patients at elevated (as planned) but only at low vascular risk and, therefore, was largely confirmatory of earlier primary prevention trials.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-20T00:00:00+01:00
      DOI: 10.1055/s-0039-1694774
       
  • Impaired Arterial Elastic Properties and Endothelial Glycocalyx in
           Patients with Embolic Stroke of Undetermined Source
    • Authors: Ikonomidis; Ignatios, Frogoudaki, Alexandra, Vrettou, Agathi-Rosa, Andreou, Ioannis, Palaiodimou, Lina, Katogiannis, Konstantinos, Liantinioti, Chryssa, Vlastos, Dimitrios, Zervas, Paschalis, Varoudi, Maria, Lambadiari, Vaia, Triantafyllidi, Helen, Pavlidis, George, Efentakis, Panagiotis, Tsoumani, Maria, Tsantes, Argirios E., Parissis, John, Revela, Ioanna, Andreadou, Ioanna, Tsivgoulis, Georgios
      Abstract: Background and Purpose Cardioembolism is a postulated mechanism of embolic stroke of undetermined source (ESUS). We investigated endothelial glycocalyx, aortic elastic properties, oxidative stress, and their association with left atrial (LA) function in ESUS and healthy individuals. Methods In 90 ESUS patients (age 50.4 ± 13.2) and 90 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5–25 µm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) LA volume and strain using speckle-tracking imaging, and (4) malondialdehyde (MDA) and protein carbonyls (PCs), as oxidative stress markers. Results Compared with controls, ESUS had higher PWV, PBR, MDA, and PC levels as well as higher LA volume and reduced reservoir LA strain (p  1.2 μm of microvessel ranging from 5 to 9 μm and PWV > 10.2 m/s were associated with ESUS on multivariable analysis (odds ratio: 2.374 and 5.429, p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-17T00:00:00+01:00
      DOI: 10.1055/s-0039-1694752
       
  • Thrombogenicity and Antithrombotic Strategies in Structural Heart
           Interventions and Nonaortic Cardiac Device Therapy—Current Evidence and
           Practice
    • Authors: Geisler; Tobias, Jorbenadze, Rezo, Popov, Aron-Frederik, Mueller, Karin L., Rath, Dominik, Droppa, Michal, Schreieck, Juergen, Seizer, Peter, Storey, Robert F., Kristensen, Steen D., Rubboli, Andrea, Gorog, Diana, Aradi, Daniel, Sibbing, Dirk, Huber, Kurt, Gawaz, Meinrad, Ten Berg, Jur
      Abstract: As the number of, and the indications for, structural heart interventions are increasing worldwide, the optimal secondary prevention to reduce device thrombosis is becoming more important. To date, most of the recommendations are empiric. The current review discusses mechanisms behind device-related thrombosis, the available evidence with regard to antithrombotic regimen after cardiac device implantation, as well as providing an algorithm for identification of risk factors for device thrombogenicity and for management of device thrombosis after implantation of patent foramen ovale and left atrial appendage occluders, MitraClips/transcatheter mitral valve replacement, pacemaker leads, and left ventricular assist devices. Of note, the topic of antithrombotic therapy and thrombogenicity of prostheses in aortic position (transcatheter aortic valve replacement, surgical, mechanical, and bioprostheses) is not part of the present article and is discussed in detail in other contemporary focused articles.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-17T00:00:00+01:00
      DOI: 10.1055/s-0039-1694751
       
  • MicroRNAs as Regulators and Biomarkers of Platelet Function and Activity
           in Coronary Artery Disease
    • Authors: Stojkovic; Stefan, Nossent, Anne Yaël, Haller, Paul, Jäger, Bernhard, Vargas, Kris G., Wojta, Johann, Huber, Kurt
      Abstract: Microribonucleic acids (miRs) are small, noncoding ribonucleic acids (RNAs), which play an important role in the regulation of platelet function and activity. Several studies proposed a mechanistic role of platelet-related miRs in the pathophysiology of coronary artery disease (CAD) and atherothrombosis. Circulating, platelet-related miRs have been proposed as diagnostic, prognostic, as well as treatment response biomarkers in CAD and acute coronary syndrome (ACS). In this review, we summarize recent studies on the role of platelet-related miRs in the regulation of platelet function and activity. Furthermore, we review the studies investigating the role of platelet-related miRs as biomarkers in patients with CAD and ACS.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-17T00:00:00+01:00
      DOI: 10.1055/s-0039-1693702
       
  • Identifying Sepsis Populations Benefitting from Anticoagulant Therapy: A
           Prospective Cohort Study Incorporating a Restricted Cubic Spline
           Regression Model
    • Authors: Yamakawa; Kazuma, Gando, Satoshi, Ogura, Hiroshi, Umemura, Yutaka, Kabata, Daijiro, Shintani, Ayumi, Shiraishi, Atsushi, Saitoh, Daizoh, Fujishima, Seitato, Mayumi, Toshihiko, Kushimoto, Shigeki, Abe, Toshikazu, Shiino, Yasukazu, Nakada, Taka-aki, Tarui, Takehiko, Hifumi, Toru, Otomo, Yasuhiro, Okamoto, Kohji, Kotani, Joji, Sakamoto, Yuichiro, Sasaki, Junichi, Shiraishi, Shin-ichiro, Takuma, Kiyotsugu, Tsuruta, Ryosuke, Hagiwara, Akiyoshi, Masuno, Tomohiko, Takeyama, Naoshi, Yamashita, Norio, Ikeda, Hiroto, Ueyama, Masashi, Fujimi, Satoshi
      Abstract: Background Anticoagulant therapy has seldom been achieved in randomized trials targeting nonspecific overall sepsis patients. Although the key components to identify the appropriate target in sepsis may be disseminated intravascular coagulation (DIC) and high disease severity, the interaction and relation of these two components for the effectiveness of therapy remain unknown. Objective This article identifies the optimal target of anticoagulant therapy in sepsis. Methods We used a prospective nationwide cohort targeting consecutive adult severe sepsis patients in 59 intensive care units in Japan to assess associations between anticoagulant therapy and in-hospital mortality according to DIC (International Society on Thrombosis and Haemostasis [ISTH] overt and Japanese Association for Acute Medicine DIC scores) and disease severity (Acute Physiology and Chronic Health Evaluation II [APACHE II] and Sequential Organ Failure Assessment scores). Multivariable Cox proportional hazard regression analysis with nonlinear restricted cubic spline including a two-way interaction term (treatment × each score) and three-way interaction term (treatment × ISTH overt DIC score × APACHE II score) was performed. Results The final study cohort comprised 1,178 sepsis patients (371 received anticoagulants and 768 did not). The regression model including the two-way interaction term showed significant interaction between intervention and disease severity as indicated by the ISTH overt DIC score and APACHE II score (p = 0.046 and p = 0.101, respectively). Three-way interaction analysis revealed that risk hazard was suppressed in the anticoagulant group compared with the control group in the most severe subset of both scores. Conclusion Anticoagulant therapy was associated with better outcome according to the deterioration of both DIC and disease severity, suggesting that anticoagulant therapy should be restricted to patients having DIC and high disease severity simultaneously.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-13T00:00:00+01:00
      DOI: 10.1055/s-0039-1693740
       
  • Antagonizing P2Y12 Receptor Inhibitors: Current and Future Options
    • Authors: Trenk; Dietmar, Hille, Laura, Leggewie, Stefan, Stratz, Christian, Nührenberg, Thomas G., Aradi, Daniel, Schrör, Karsten, Sibbing, Dirk
      Abstract: There are clinical scenarios where the balance between the risk of ischemic and bleeding events leads to the clinical decision to reverse the antiplatelet effect of P2Y12 receptor inhibitors. These scenarios comprise emergency situations such as active severe bleeding, urgent procedures with presumed high bleeding risk, or major trauma with (anticipated) bleeding. Supplementation of platelets has been investigated in ex vivo as well as in in vivo studies. These studies indicate that the inhibition of adenosine diphosphate-induced aggregation by the irreversibly binding thienopyridine derivatives clopidogrel and prasugrel can be reversed by administration of platelet concentrates. Supplementation of platelets in patients on prasugrel is more effective if this can be transfused > 6 hours after last dosing. Studies on the reversal effect obtained by administration of platelet concentrates in patients on ticagrelor show conflicting results. Experimental data suggest that administration of serum albumin might increase the reversal effect. A monoclonal antibody fragment (PB2452) for neutralizing ticagrelor is currently in clinical development. A recently published first in man study shows that reversal of platelet inhibition occurs within 5 minutes after start of administration and the effect is maintained for 20 to 24 hours after a 16-hour infusion which is by far the most effective approach for reversal of ticagrelor.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-13T00:00:00+01:00
      DOI: 10.1055/s-0039-1693738
       
  • Recurrence Risk in Patients with Cryptogenic Stroke, Patent Foramen Ovale,
           and Thrombophilia: A Systematic Review and Meta-Analysis
    • Authors: Hviid; Claus V. B., Simonsen, Claus Ziegler, Hvas, Anne-Mette
      Abstract: Objective A patent foramen ovale (PFO) is frequently associated with cryptogenic stroke in the young. Endovascular closure is superior to antithrombotic treatment in prevention of recurrence, but in the presence of a concomitant thrombophilia, the best preventive strategy is unknown. This review investigates if thrombophilia increases the risk of recurrence in patients with cryptogenic stroke and PFO and attempts to evaluate the best antithrombotic strategy after PFO closure in these patients. Methods Medline, Embase, and Web of Science were searched until April 2018. Study quality was assessed by the National Heart, Lung and Blood Institute Quality assessment tool. Odds ratio (OR) and hazard ratio for recurrence were pooled in a random effect model stratified by secondary preventive strategy. Results Eleven studies were included. Inherited or acquired thrombophilia was associated with an increased risk of recurrence (OR = 2.41, 95% confidence interval [CI]: 1.44–4.06). Looking only at patients treated with PFO closure, the risk of recurrence just lost significance (OR = 2.07, 95% CI: 0.95–4.48). The antithrombotic treatment after PFO closure was heterogeneous and recurrent events occurred in patients with both inherited and acquired thrombophilia treated by antiplatelet as well as anticoagulant therapy. Conclusion Thrombophilia is associated with an increased risk of recurrence in patients with PFO and cryptogenic stroke, which may persist after PFO closure. This suggests a need for antithrombotic therapy after PFO closure. Study heterogeneity precludes strong conclusions on antithrombotic treatment, but life-long antiplatelet therapy to patients without preexisting indication for anticoagulant therapy seems reasonable.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-04T00:00:00+01:00
      DOI: 10.1055/s-0039-1693739
       
  • Platelet PI3K Modulates Innate Leukocyte Extravasation during Acid-Induced
           Acute Lung Inflammation
    • Authors: Kral-Pointner; Julia Barbara, Schrottmaier, Waltraud Cornelia, Salzmann, Manuel, Mussbacher, Marion, Schmidt, Georg Johannes, Moser, Bernhard, Heber, Stefan, Birnecker, Birgit, Paar, Hannah, Zellner, Maria, Knapp, Sylvia, Assinger, Alice, Schabbauer, Gernot
      Abstract: Introduction Blood platelets are increasingly recognized as modulators of leukocyte effector functions in various pathologies including acute lung injury (ALI). ALI is a life-threatening disease, caused by damage to the alveolar epi- and endothelium. Excessive accumulation of leukocytes leads to severe lung inflammation, resulting in impaired lung function and hypoxemia. Objective Since leukocyte migration is modulated by activated platelets and phosphatidylinositol 3-kinase (PI3K) signaling is involved in platelet function, we aimed to elucidate the effect of PI3K on platelet-mediated immune responses. Materials and Methods We generated a mouse model with a platelet-specific deletion of p85α, the most important regulatory subunit of the class IA PI3K, and evaluated platelet function and platelet–leukocyte interactions. Moreover, we analyzed the impact of platelet-specific p85α gene deficiency during sterile peritonitis and acid-induced ALI. Results In vitro analyses of platelets revealed that lack of p85α led to decreased downstream signaling and diminished expression of surface activation markers, for example, CD62P and CD63, as well as reduced platelet aggregation. Moreover, platelet PI3K essentially mediated direct interactions of platelets with monocytes and neutrophils. In mice, platelet-specific p85α deficiency prevented leukocyte infiltration into the peritoneum and the bronchoalveolar compartment during sterile peritonitis and ALI, respectively. Additionally, the release of the inflammatory cytokine interleukin-12/23 was diminished in platelet p85α-deficient mice during ALI. In contrast to PI3K, neither overexpression nor depletion of platelet phosphatase and tensin homolog, the endogenous antagonist of PI3K, significantly modulated platelet function. Conclusion Our data indicate a crucial role of platelet PI3K signaling for leukocyte extravasation upon inflammatory stimuli in various diseases models.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-01T00:00:00+01:00
      DOI: 10.1055/s-0039-1693693
       
  • All-Trans Retinoic Acid Impairs Platelet Function and Thrombus Formation
           and Inhibits Protein Kinase CßI/δ Phosphorylation
    • Authors: Luo; Qi, Wei, Guangyu, Wang, Xiamin, Xu, Xiaoqi, Ju, Wen, Li, Zhenyu, Gardiner, Elizabeth E., Andrews, Robert K., Zeng, Lingyu, Xu, Kailin, Qiao, Jianlin
      Abstract: All-trans retinoic acid (ATRA) is widely used for induction of complete remission in patients with acute promyelocytic leukemia (APL). ATRA also regulates protein kinase C (PKC) activity. Therapeutic use of ATRA reportedly interferes with hemostatic function in APL patients, including effects on coagulation or other vascular cells, although effects of ATRA on platelets remain unclear. This study aims to investigate the effect of therapeutic-relevant doses of ATRA on platelet function. Human platelets were preincubated with ATRA (0–20 μM) for 1 hour at 37°C, followed by analysis of aggregation, granule secretion, receptor expression by flow cytometry, platelet spreading, or clot retraction. Additionally, ATRA (10 mg/kg) was injected intraperitoneally into mice and tail bleeding time and arterial thrombus formation were evaluated. ATRA inhibited platelet aggregation and adenosine triphosphate release induced by collagen (5 μg/mL) or thrombin (0.05 U/mL) in a dose-dependent manner without affecting P-selectin expression or surface levels of glycoprotein (GP) Ibα, GPVI, or αIIbβ3. ATRA-treated platelets demonstrated reduced spreading on immobilized fibrinogen or collagen and reduced thrombin-induced clot retraction together with reduced phosphorylation of Syk and PLCγ2. In addition, ATRA-treated mice displayed significantly impaired hemostasis and arterial thrombus formation in vivo. Further, in platelets stimulated with either collagen-related peptide or thrombin, ATRA selectively inhibited phosphorylation of PKCßI (Ser661) and PKCδ (Thr505), but not PKCα or PKCßII phosphorylation (Thr638/641). In conclusion, ATRA inhibits platelet function and thrombus formation, possibly involving direct or indirect inhibition of PKCßI/δ, indicating that ATRA might be beneficial for the treatment of thrombotic or cardiovascular diseases.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-01T00:00:00+01:00
      DOI: 10.1055/s-0039-1693737
       
  • Quality of Warfarin Therapy and Quality of Life are Improved by
           Self-Management for Two Years
    • Authors: Sølvik; Una Ørvim, Løkkebø, Elisabeth, Kristoffersen, Ann Helen, Brodin, Ellen, Averina, Maria, Sandberg, Sverre
      Abstract: Background Studies from several countries show that self-management of vitamin K antagonist (e.g., warfarin) therapy reduce the risk of complications compared with conventional management. Objectives The aim of this study was to investigate the quality of warfarin management when patients were transferred from conventional management to self-management in Norway. In addition, quality of life (QoL) before and after 2 years of warfarin self-management was investigated. Materials and Methods The study was longitudinal with a retrospective and prospective design where 126 patients on conventional management of long-term warfarin therapy underwent a 21-week training program of warfarin self-management followed by 2 years of self-management. The outcomes of the study were time in therapeutic range (TTR), the variance of international normalized ratio (INR) values, extreme INR values (INR ≤ 1.5 and ≥ 5), complications, and QoL, comparing the 2-year period of the conventional management with the 2-year period with the self-management. Results The median TTR was higher during self-management compared with conventional management (78.1% vs. 65.9%, respectively, p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-01T00:00:00+01:00
      DOI: 10.1055/s-0039-1693703
       
  • Isolated Distal Deep Vein Thrombosis: Perspectives from the GARFIELD-VTE
           Registry
    • Authors: Schellong; Sebastian M., Goldhaber, Samuel Z., Weitz, Jeffrey I., Ageno, Walter, Bounameaux, Henri, Turpie, Alexander G. G., Angchaisuksiri, Pantep, Haas, Sylvia, Goto, Shinya, Zaghdoun, Audrey, Farjat, Alfredo, Nielsen, Joern Dalsgaard, Kayani, Gloria, Mantovani, Lorenzo G., Prandoni, Paolo, Kakkar, Ajay K.
      Abstract: Isolated distal deep vein thrombosis (IDDVT) represents up to half of all lower limb DVT. This study investigated treatment patterns and outcomes in 2,145 patients with IDDVT in comparison with those with proximal DVT (PDVT; n = 3,846) and pulmonary embolism (PE; n = 4,097) enrolled in the GARFIELD-VTE registry. IDDVT patients were more likely to have recently undergone surgery (14.6%) or experienced leg trauma (13.2%) than PDVT patients (11.0 and 8.7%, respectively) and PE patients (12.7 and 4.5%, respectively). Compared with IDDVT, patients with PDVT or PE were more likely to have active cancer (7.2% vs. 9.9% and 10.3%). However, influence of provoking factors on risk of recurrence in IDDVT remains controversial. Nearly all patients (IDDVT, PDVT, and PE) were given anticoagulant therapy. In IDDVT, PDVT, and PE groups the proportion of patients receiving anticoagulant therapy was 61.4, 73.9, and 81.1% at 6 months and 45.8, 54.7, and 61.9% at 12 months. Over 12 months, the incidence of all-cause mortality, cancer, and recurrence was significantly lower in IDDVT patients than PDVT patients (hazard ratio [HR], 0.61 [95% confidence interval [CI], 0.48–0.77]; sub-HR [sHR], 0.60 [95% CI, 0.39–0.93]; and sHR, 0.76 [95% CI, 0.60–0.97]). Likewise, risk of death and incident cancer was significantly (both p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-08-01T00:00:00+01:00
      DOI: 10.1055/s-0039-1693461
       
  • Geographical Variations in Patterns of DAPT Cessation and Two-Year PCI
           Outcomes: Insights from the PARIS Registry
    • Authors: Vogel; Birgit, Chandrasekhar, Jaya, Baber, Usman, Mastoris, Ioannis, Sartori, Samantha, Aquino, Melissa, Krucoff, Mitchell W., Moliterno, David J., Henry, Timothy D., Weisz, Giora, Gibson, C Michael, Iakovou, Ioannis, Kini, Annapoorna S., Farhan, Serdar, Sorrentino, Sabato, Faggioni, Michela, Colombo, Antonio, Steg, Philippe Gabriel, Witzenbichler, Bernhard, Chieffo, Alaide, Cohen, David J., Stuckey, Thomas, Ariti, Cono, Dangas, George D., Pocock, Stuart, Mehran, Roxana
      Abstract: Background Data on geographical variations in dual antiplatelet therapy (DAPT) cessation and the impact on outcomes after percutaneous coronary intervention (PCI) are limited. We sought to evaluate geographical patterns of DAPT cessation and associated outcomes in patients undergoing PCI in the United States versus Europe. Methods Analyzing data from the PARIS registry, we studied 3,660 U.S. patients (72.9%) and 1,358 European patients (27.1%) that underwent PCI with stent implantation. DAPT cessation was classified as physician-recommended discontinuation, interruption (< 14 days), or disruption due to bleeding or noncompliance. The primary endpoint was 2-year major adverse cardiovascular events (MACE) defined as a composite of cardiac death, stent thrombosis, myocardial infarction, or target lesion revascularization. Results Cardiovascular risk factors were more common in the United States, whereas procedural complexity was greater in Europe. The incidence of 2-year DAPT discontinuation was significantly lower in U.S. versus European patients (30.7% vs. 65.6%; p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-07-31T00:00:00+01:00
      DOI: 10.1055/s-0039-1693463
       
  • The Effect of Flucloxacillin on Warfarin Anticoagulation: A Swedish
           Register-Based Nationwide Cohort Study
    • Authors: Mannheimer; Buster, Stage, Tore B., Pottegård, Anton, Lindh, Jonatan D.
      Abstract: Background Data indicate that codispensing flucloxacillin to patients already on warfarin may result in decreased warfarin efficacy. Objectives This article investigates the effect of flucloxacillin on warfarin anticoagulation. Patients and Methods In a retrospective cohort study of warfarin users, using three nationwide registers we included 5,848 patients receiving 10 days flucloxacillin treatment and 201 with ≥30 days treatment. To assess the potential for confounding by indication, we also identified 21,430 individuals initiating phenoxymethylpenicillin. International normalized ratio (INR) values and warfarin doses were calculated day-by-day and proportion of patients with a subtherapeutic INR week-by-week during cotreatment. Results Following initiation of flucloxacillin with a planned treatment duration of 10 days and ≥30 days, the mean INR decreased from 2.36 (95% confidence interval [CI] 2.34; 2.37) to 2.20 (95% CI 2.19; 2.21) and from 2.24 (95% CI 2.16; 2.32) to 1.96 (95% CI 1.89; 2.02), respectively. Consequently, for individuals with 10 days treatment the proportion of patients with a subtherapeutic INR of 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-07-28T00:00:00+01:00
      DOI: 10.1055/s-0039-1693462
       
  • Total Thrombus-Formation Analysis System (T-TAS): Clinical Application of
           Quantitative Analysis of Thrombus Formation in Cardiovascular Disease
    • Authors: Kaikita; Koichi, Hosokawa, Kazuya, Dahlen, Jeffrey R., Tsujita, Kenichi
      Abstract: Various antithrombotic agents are clinically used to inhibit the cascade of arterial or venous thrombosis in cardiovascular diseases. Dual antiplatelet therapy with aspirin and P2Y12 inhibitors is prescribed in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). Direct oral anticoagulants (DOACs) are widely used for the prevention or treatment of thromboembolism in patients with atrial fibrillation (AF) and venous thromboembolism. However, there has been no definitive tool to simultaneously monitor the antithrombotic effects of these drugs. The Total Thrombus-Formation Analysis System (T-TAS), a microchip-based flow chamber system that mimics in vivo conditions for evaluating whole blood thrombogenicity, was developed for the quantitative analysis of thrombus formation in whole blood specimens. The utility of T-TAS has been evaluated in CAD patients treated with antiplatelet therapies. The T-TAS PL chip area under the flow pressure curve (AUC) accurately assesses primary hemostasis and is sensitive to the therapeutic effects of various antiplatelet therapies. In addition, low AUC results are a significant predictor of periprocedural bleeding events in CAD patients undergoing PCI. The T-TAS AR chip AUC result is useful for assessing the efficacy of DOACs and warfarin in AF patients undergoing catheter ablation, and it is also a potential independent predictor of periprocedural bleeding events and avoidance of thrombosis in patients having undergone total knee arthroplasty. In conclusion, T-TAS is a useful index for evaluating the total antithrombotic effects of combination antithrombotic agents in patients with various cardiovascular diseases.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-07-22T00:00:00+01:00
      DOI: 10.1055/s-0039-1693411
       
  • Improved Population-Based Clinical Outcomes of Patients with Atrial
           Fibrillation by Compliance with the Simple ABC (Atrial Fibrillation Better
           Care) Pathway for Integrated Care Management: A Nationwide Cohort Study
    • Authors: Yoon; Minjae, Yang, Pil-Sung, Jang, Eunsun, Yu, Hee Tae, Kim, Tae-Hoon, Uhm, Jae-Sun, Kim, Jong-Youn, Sung, Jung-Hoon, Pak, Hui-Nam, Lee, Moon-Hyoung, Joung, Boyoung, Lip, Gregory Y. H.
      Abstract: Background An integrated care approach might be of benefit for clinical outcomes of patients with atrial fibrillation (AF). This study evaluated whether compliance with the Atrial fibrillation Better Care (ABC) pathway for integrated care management (“A” Avoid stroke; “B” Better symptom management; “C” Cardiovascular risk and Comorbidity optimization) would improve population-based clinical outcomes in a nationwide AF cohort. Methods and Results From the Korea National Health Insurance Service database, a total of 204,842 nonvalvular AF patients were enrolled between January 1, 2005 and December 31, 2015. Patients that fulfilled all criteria of the ABC pathway were defined as the “ABC” group, and those who did not were the “Non-ABC” group.Over a mean follow-up of 6.2 ± 3.5 years, the ABC pathway compliant group had lower rates of all-cause death (0.80 vs. 2.72 per 100 person-years, p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-07-02T00:00:00+01:00
      DOI: 10.1055/s-0039-1693516
       
  • Dual Antiplatelet or Dual Antithrombotic Therapy for Secondary Prevention
           in High-Risk Patients with Stable Coronary Artery Disease'
    • Authors: Sumaya; Wael, Geisler, Tobias, Kristensen, Steen D., Storey, Robert F.
      Abstract: Antithrombotic treatment is a key component of secondary prevention following acute coronary syndromes (ACS). Although dual antiplatelet therapy is standard therapy post-ACS, duration of treatment is the subject of ongoing debate. Prolonged dual antiplatelet therapy in high-risk patients with history of myocardial infarction reduced the risk of recurrent myocardial infarction, stroke or cardiovascular death. Similarly, in patients with stable coronary artery disease, two-thirds of whom had a history of myocardial infarction, dual antithrombotic therapy with very-low-dose rivaroxaban and aspirin also resulted in improved ischaemic outcomes. In the absence of head-to-head comparison, choosing the most appropriate treatment strategy can be challenging, particularly when it comes to balancing the risks of ischaemia and bleeding. We aim to review the evidence for currently available antithrombotic treatments and provide a practical algorithm to aid the decision-making process.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-03-05T00:00:00+0100
      DOI: 10.1055/s-0039-1679903
       
 
 
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