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Thrombosis & Haemostasis
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ISSN (Print) 0340-6245 - ISSN (Online) 2567-689X
Published by Thieme Publishing Group Homepage  [239 journals]
  • What's the Matter with Distal Deep Vein Thrombosis'
    • Thromb Haemost 2019; 19: 1547-1549
      DOI: 10.1055/s-0039-1696983



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 19: 1547-15492019-09-29T00:00:00+01:00
      Issue No: Vol. 19, No. 10 (2019)
       
  • Warfarin Therapy and Improved Anticoagulation Control by Patient
           Self-Management
    • Thromb Haemost 2019; 19: 1550-1552
      DOI: 10.1055/s-0039-1696982



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 19: 1550-15522019-09-29T00:00:00+01:00
      Issue No: Vol. 19, No. 10 (2019)
       
  • Platelets: The Balance between Aggregation and Bleeding
    • Thromb Haemost 2019; 19: 1553-1553
      DOI: 10.1055/s-0039-1696984



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 19: 1553-15532019-09-29T00:00:00+01:00
      Issue No: Vol. 19, No. 10 (2019)
       
  • Modeling Complexity: The Case of Cancer-Related Venous Thromboembolism
    • Thromb Haemost 2019; 119: 1713-1715
      DOI: 10.1055/s-0039-1700543



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 119: 1713-17152019-10-30T00:00:00+0100
      Issue No: Vol. 119, No. 11 (2019)
       
  • Venous Thromboembolism Prophylaxis: Safe, but Still Provocative'
    • Thromb Haemost 2019; 119: 1716-1718
      DOI: 10.1055/s-0039-1700564



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 119: 1716-17182019-10-30T00:00:00+0100
      Issue No: Vol. 119, No. 11 (2019)
       
  • Fibrin Degradation Product β15-42—New Insights in an Old
           Pathway
    • Thromb Haemost 2019; 119: 1719-1719
      DOI: 10.1055/s-0039-1700544



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost 2019; 119: 1719-17192019-10-30T00:00:00+0100
      Issue No: Vol. 119, No. 11 (2019)
       
  • Platelet Function Changes during Neonatal Cardiopulmonary Bypass Surgery:
           Mechanistic Basis and Lack of Correlation with Excessive Bleeding
    • Authors: Zwifelhofer; Nicole M. J., Bercovitz, Rachel S., Cole, Regina, Yan, Ke, Simpson, Pippa M., Moroi, Alyssa, Newman, Peter J., Niebler, Robert A., Scott, John P., Stuth, Eckehard A. D., Woods, Ronald K., Benson, D. Woodrow, Newman, Debra K.
      Abstract: Thrombocytopenia and platelet dysfunction induced by extracorporeal blood circulation are thought to contribute to postsurgical bleeding complications in neonates undergoing cardiac surgery with cardiopulmonary bypass (CPB). In this study, we examined how changes in platelet function relate to changes in platelet count and to excessive bleeding in neonatal CPB surgery. Platelet counts and platelet P-selectin exposure in response to agonist stimulation were measured at four times before, during, and after CPB surgery in neonates with normal versus excessive levels of postsurgical bleeding. Relative to baseline, platelet counts were reduced in patients while on CPB, as was platelet activation by the thromboxane A2 analog U46619, thrombin receptor activating peptide (TRAP), and collagen-related peptide (CRP). Platelet activation by adenosine diphosphate (ADP) was instead reduced after platelet transfusion. We provide evidence that thrombocytopenia is a likely contributor to CPB-associated defects in platelet responsiveness to U46619 and TRAP, CPB-induced collagen receptor downregulation likely contributes to defective platelet responsiveness to CRP, and platelet transfusion may contribute to defective platelet responses to ADP. Platelet transfusion restored to baseline levels platelet counts and responsiveness to all agonists except ADP but did not prevent excessive bleeding in all patients. We conclude that platelet count and function defects are characteristic of neonatal CPB surgery and that platelet transfusion corrects these defects. However, since CPB-associated coagulopathy is multifactorial, platelet transfusion alone is insufficient to treat bleeding events in all patients. Therefore, platelet transfusion must be combined with treatment of other factors that contribute to the coagulopathy to prevent excessive bleeding.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-11-21T00:00:00+0100
      DOI: 10.1055/s-0039-1700517
       
  • Interpretation and Validation of Maximum Absorbance Data Obtained from
           Turbidimetry Analysis of Plasma Clots
    • Authors: Pieters; Marlien, Guthold, Martin, Nunes, Claudia M., de Lange, Zelda
      Abstract: Turbidimetry is used to characterize fibrin clot properties. In purified systems, maximum absorbance (MA) directly relates to fibrin fiber cross-sectional area. However, in plasma samples there are discrepancies in the relationships between MA and fibrinogen concentration, fiber diameter, other clot properties, and cardiovascular disease outcomes, which complicate data interpretation. This study aims to advance understanding of MA of plasma clots through testing how well it relates to fundamental dependence on fibrinogen concentration and fiber diameter as predicted by light scattering theory, other clot properties and lifestyle, and biochemical variables. Plasma samples from 30 apparently healthy individuals with a fibrinogen concentration from 2.4 to 6.4 g/L were included. We performed turbidimetry, permeability, scanning electron microscopy, and rheometry on in vitro formed plasma clots. MA correlated more strongly with fibrinogen concentration (r = 0.65; p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-11-21T00:00:00+0100
      DOI: 10.1055/s-0039-1698460
       
  • Efficacy and Safety of Glycoprotein IIb/IIIa Inhibitors on Top of
           Ticagrelor in STEMI: A Subanalysis of the ATLANTIC Trial
    • Authors: Tavenier; Anne H., Hermanides, Renicus S., Fabris, Enrico, Lapostolle, Frédéric, Silvain, Johanne, ten Berg, Jurrien M., Lassen, Jens F., Bolognese, Leonardo, Cantor, Warren J., Cequier, Ángel, Chettibi, Mohamed, Goodman, Shaun G., Hammett, Christopher J., Huber, Kurt, Janzon, Magnus, Merkely, Béla, Storey, Robert F., Zeymer, Uwe, Ecollan, Patrick, Collet, Jean-Phillipe, Willems, Frank F., Diallo, Abdourahmane, Vicaut, Eric, Hamm, Christian W., Montalescot, Gilles, van 't Hof, Arnoud W. J.
      Abstract: Background Glycoprotein IIb/IIIa inhibitors (GPIs) in combination with clopidogrel improve clinical outcome in ST-elevation myocardial infarction (STEMI); however, finding a balance that minimizes both thrombotic and bleeding risk remains fundamental. The efficacy and safety of GPI in addition to ticagrelor, a more potent P2Y12-inhibitor, have not been fully investigated. Methods 1,630 STEMI patients who underwent primary percutaneous coronary intervention (PCI) were analyzed in this subanalysis of the ATLANTIC trial. Patients were divided in three groups: no GPI, GPI administration routinely before primary PCI, and GPI administration in bailout situations. The primary efficacy outcome was a composite of death, myocardial infarction, urgent target revascularization, and definite stent thrombosis at 30 days. The safety outcome was non-coronary artery bypass graft (CABG)-related PLATO major bleeding at 30 days. Results Compared with no GPI (n = 930), routine GPI (n = 525) or bailout GPI (n = 175) was not associated with an improved primary efficacy outcome (4.2% no GPI vs. 4.0% routine GPI vs. 6.9% bailout GPI; p = 0.58). After multivariate analysis, the use of GPI in bailout situations was associated with a higher incidence of non-CABG-related bleeding compared with no GPI (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.32–6.64; p = 0.03). However, routine GPI use compared with no GPI was not associated with a significant increase in bleeding (OR 1.78, 95% CI 0.88–3.61; p = 0.92). Conclusion Use of GPIs in addition to ticagrelor in STEMI patients was not associated with an improvement in 30-day ischemic outcome. A significant increase in 30-day non-CABG-related PLATO major bleeding was seen in patients who received GPIs in a bailout situation.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-11-21T00:00:00+0100
      DOI: 10.1055/s-0039-1700546
       
  • The Pointy End of Point-of-Care Testing for Direct Oral Anticoagulants
    • Thromb Haemost
      DOI: 10.1055/s-0039-1700874



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost ; : -2019-11-21T00:00:00+0100
       
  • Imbalance between Fibrin Clot Formation and Fibrinolysis Predicts
           Cardiovascular Events in Patients with Stable Coronary Artery Disease
    • Authors: Neergaard-Petersen; Søs, Larsen, Sanne B., Grove, Erik L., Kristensen, Steen D., Ajjan, Ramzi A., Hvas, Anne-Mette
      Abstract: Background Despite long-term antiplatelet therapy with aspirin, recurrent cardiovascular events remain common in patients with coronary artery disease (CAD). Objective We aimed to determine whether fibrin network characteristics are predictive of vascular events in patients with stable CAD treated with aspirin monotherapy. Methods We included 786 patients with angiographically documented CAD and either prior myocardial infarction, type 2 diabetes mellitus, or both. Median follow-up time was 3 years. At inclusion, fibrin clot properties were evaluated using a turbidimetric assay and the following clot parameters were studied: (1) maximum absorbance, a measure of clot density and fiber thickness; (2) lysis time, assessing fibrinolysis potential; and (3) area under the curve (AUC), a measure of clot formation and lysis. The primary endpoint was the composite of nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. Hazard ratios (HRs) were estimated using multivariable Cox proportional hazards regression. Results A total of 70 primary endpoints occurred. The primary endpoint occurred more frequently in CAD patients with increased clot AUC (crude HR for first vs. fourth quartile: 2.4 [95% confidence interval 1.2–4.6], p = 0.01). This finding remained significant after adjusting for potential confounders (adjusted HR: 2.4 [1.2–4.8], p = 0.01). Neither clot maximum absorbance nor lysis time showed significant association with future vascular events (adjusted HR for maximum absorbance 1.8 [0.9–3.7]; p = 0.09) and lysis time (1.6 [0.8–3.0]; p = 0.18). Conclusion We demonstrate that increased clot AUC predicts future cardiovascular events in stable CAD patients receiving aspirin monotherapy.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-11-16T00:00:00+0100
      DOI: 10.1055/s-0039-1700873
       
  • PBMCs-Derived microRNA Signature as a Prethrombotic Status Discriminator
           in Stable Coronary Artery Disease
    • Authors: Gao; Jie, Liu, Jia, Zhang, Ying, Guan, BaoYi, Qu, Hua, Chai, Hua, Wang, WenTing, Ma, XiaoJuan, Shi, DaZhuo
      Abstract: Prethrombotic status (PTS) in patients with stable coronary artery disease (SCAD) increases the risk of coronary thrombosis. Accumulating evidences have indicated that micro-ribonucleic acids (miRNAs) may serve as promising biomarkers for SCAD patients with PTS. The present study aimed to identify the miRNA signature in SCAD patients with PTS and evaluated their diagnostic significance. In the screening phase, 32 differently expressed miRNAs (DEMs) in peripheral blood mononuclear cells (PBMCs) were detected in 35 SCAD patients compared with 5 healthy controls by microarray. MiRNA-gene network analysis was then performed, and 4 DEMs were selected for validation with reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) test in an independent cohort comprising 79 SCAD patients and 19 healthy controls. Compared with healthy controls, RT-qPCR test verified the upregulations of miR-34a-5p, miR-432–5p, and miR-370–3p detected by microarray; while the upregulation of miR-495–3p measured by RT-qPCR was not consistent with its low expression detected by microarray. Only miR-34a-5p and miR-495–3p were significantly upregulated in the PTS group compared with the non-PTS group (p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-11-12T00:00:00+0100
      DOI: 10.1055/s-0039-1700518
       
  • Urokinase Plasminogen Activator Overexpression Reverses Established Lung
           Fibrosis
    • Authors: Horowitz; Jeffrey C., Tschumperlin, Daniel J., Kim, Kevin K., Osterholzer, John J., Subbotina, Natalya, Ajayi, Iyabode O., Teitz-Tennenbaum, Seagal, Virk, Ammara, Dotson, Megan, Liu, Fei, Sicard, Delphine, Jia, Shijing, Sisson, Thomas H.
      Abstract: Introduction Impaired plasminogen activation (PA) is causally related to the development of lung fibrosis. Prior studies demonstrate that enhanced PA in the lung limits the severity of scarring following injury and in vitro studies indicate that PA promotes matrix degradation and fibroblast apoptosis. These findings led us to hypothesize that increased PA in an in vivo model would enhance the resolution of established lung fibrosis in conjunction with increased myofibroblast apoptosis. Methods Transgenic C57BL/6 mice with doxycycline inducible lung-specific urokinase plasminogen activator (uPA) expression or littermate controls were treated (day 0) with bleomycin or saline. Doxycycline was initiated on days 1, 9, 14, or 21. Lung fibrosis, stiffness, apoptosis, epithelial barrier integrity, and inflammation were assessed. Results Protection from fibrosis with uPA upregulation from day 1 through day 28 was associated with reduced parenchymal stiffness as determined by atomic force microscopy. Initiation of uPA expression beginning in the late inflammatory or the early fibrotic phase reduced stiffness and fibrosis at day 28. Induction of uPA activity in mice with established fibrosis decreased lung collagen and lung stiffness while increasing myofibroblast apoptosis. Upregulation of uPA did not alter lung inflammation but was associated with improved epithelial cell homeostasis. Conclusion Restoring intrapulmonary PA activity diminishes lung fibrogenesis and enhances the resolution of established lung fibrosis. This PA-mediated resolution is associated with increased myofibroblast apoptosis and improved epithelial cell homeostasis. These studies support the potential capacity of the lung to resolve existing scar in murine models.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-11-08T00:00:00+0100
      DOI: 10.1055/s-0039-1697953
       
  • Development of a Plasma-Based Assay to Measure the Susceptibility of
           Factor V to Inhibition by the C-Terminus of TFPIα
    • Authors: van Doorn; Peter, Rosing, Jan, Campello, Elena, Middeldorp, Saskia, Simioni, Paolo, Meijers, Joost C. M., Hackeng, Tilman M., Castoldi, Elisabetta
      Abstract: Background Factor V (FV) is proteolytically activated to FVa, which assembles with FXa in the prothrombinase complex. The C-terminus of tissue factor pathway inhibitor-α (TFPIα) inhibits both the activation and the prothrombinase activity of FV(a), but the pathophysiological relevance of this anticoagulant mechanism is unknown. FV Leiden (FVL) is less susceptible to inhibition by TFPIα, while overexpression of FV splicing variants with increased affinity for TFPIα (FV-short) causes bleeding. Objective This study aims to develop a plasma-based assay that quantifies the susceptibility of FV(a) to inhibition by the TFPIα C-terminus. Materials and Methods FV in highly diluted plasma was preactivated with FXa in the absence or presence of the TFPIα C-terminal peptide. After adding prothrombin, thrombin formation was monitored continuously with a chromogenic substrate and prothrombinase rates were obtained from parabolic fits of the absorbance tracings. TFPI resistance was expressed as the ratio of the prothrombinase rates with and without peptide (TFPIr). Results The TFPIr (0.25–0.34 in 45 healthy volunteers) was independent of FV levels. The TFPIr increased from normal individuals (0.29, 95% confidence interval [CI] 0.28–0.31) to FVL heterozygotes (0.35, 95% CI 0.34–0.37) and homozygotes (0.39, 95% CI 0.37–0.40), confirming TFPI resistance of FVL. Two individuals overexpressing FV-shortAmsterdam had markedly lower TFPIr (0.16, 0.18) than a normal relative (0.29), in line with the high affinity of FV-short for TFPIα. Conclusion We have developed and validated an assay that measures the susceptibility of plasma FV to the TFPIα C-terminus. Once automated, this assay may be used to test whether the TFPIr correlates with thrombosis or bleeding risk in population studies.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-11-08T00:00:00+0100
      DOI: 10.1055/s-0039-1700516
       
  • Stent Thrombosis after Endovascular Treatment of Iliofemoral or Caval
           Veins in Patients with Postthrombotic Syndrome
    • Thromb Haemost
      DOI: 10.1055/s-0039-1700808



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost ; : -2019-11-08T00:00:00+0100
       
  • George J. Broze Jr., MD (2 August, 1946–19 June, 2019)
    • Thromb Haemost
      DOI: 10.1055/s-0039-1697618



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost ; : -2019-11-08T00:00:00+0100
       
  • Accuracy of a Rapid Diagnostic Test for the Presence of Direct Oral Factor
           Xa or Thrombin Inhibitors in Urine—A Multicenter Trial
    • Authors: Harenberg; Job, Beyer-Westendorf, Jan, Crowther, Mark, Douxfils, Jonathan, Elalamy, Ismail, Verhamme, Peter, Bauersachs, Rupert, Hetjens, Svetlana, Weiss, Christel
      Abstract: The rapid determination of the presence of direct oral anticoagulants (DOACs) in a patient remains a major challenge in emergency medicine and for rapid medical treatment decisions. All DOACs are excreted into urine. A sensitive and specific point-of-care test has been developed to determine whether they are present in patient urine samples. This prospective multicenter study aimed to demonstrate at least 95% correct positive and negative predictive results for factor Xa and thrombin inhibitors in urine samples using DOAC Dipstick pads compared with liquid chromatography-tandem mass spectrometry (LC-MS/MS) (NCT03182829). Nine hundred and fourteen subjects were included and 880 were evaluated per protocol (factor Xa inhibitors apixaban, edoxaban, and rivaroxaban: n = 451, thrombin inhibitor dabigatran: n = 429) at 18 centers. The sensitivity, specificity, accuracy, and predictive values and agreement between methods for determination of factor Xa inhibitors were at least noninferior to 95% with a 0.5% margin and of thrombin inhibitor superior to 97.5%. These results were compared with LC-MS/MS results in the intention-to-analyze cohort (all p 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-11-08T00:00:00+0100
      DOI: 10.1055/s-0039-1700545
       
  • Recombinant Adeno-Associated Viral Vectors Expressing Human Coagulation
           FIX-E456H Variant in Hemophilia B Mice
    • Authors: Le Quellec; Sandra, Dane, Allison P., Barbon, Elena, Bordet, Jean-Claude, Mingozzi, Federico, Dargaud, Yesim, Marais, Thibaut, Biferi, Maria-Grazia, Négrier, Claude, Nathawani, Amit C., Enjolras, Nathalie
      Abstract: Gene therapy using recombinant adeno-associated virus (AAV) has induced sustained long-term coagulation human factor IX (hFIX) levels in hemophilia B (HB) patients. However, asymptomatic transient liver toxicity was observed at high vector doses, highlighting the need to improve the potency of these vectors. We report the generation of an AAV transgene cassette containing the hyperfunctional hFIX-E456H variant showing improved binding to platelets, with a comparison to wild-type hFIX (hFIX-WT) and hFIX-R384L variant (Padua) transgenes, containing F9 truncated-intron 1 (I1). In vitro specific activity was increased by 3.2- and 4.2-fold with hFIX-E456H and hFIX-R384L variants compared with hFIX-WT, using chromogenic assay, and by 7-and 8.6-fold with hFIX-E456H and hFIX-R384L variants compared with hFIX-WT, using one-stage assay. The transgenes were packaged into single-stranded AAV2/8 vectors that were tail vein injected at 5 × 109, 2 × 1010, and 5 × 1010 vg per mouse in HB mice. Plasma FIX activity level, assessed by chromogenic assay, was up to fourfold higher for hFIX-E456H compared with hFIX-WT and was not different compared with hFIX-R384L, among the three dose cohorts. Overall, the in vivo specific activity was increased by threefold for hFIX-E456H and 4.9-fold for hFIX-R384L compared with hFIX-WT. At the lower dose of 5 × 109 vg, the blood loss was significantly lower for hFIX-E456H compared with hFIX-WT, but did not differ compared with hFIX-R384L. The results found for the hFIX-E456H variant indicate that it might be a suitable alternative for gene therapy of HB.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-28T00:00:00+0100
      DOI: 10.1055/s-0039-1697658
       
  • Longitudinally Measured Fibrinolysis Factors are Strong Predictors of
           Clinical Outcome in Patients with Chronic Heart Failure: The Bio-SHiFT
           Study
    • Authors: van den Berg; Victor J., Bouwens, Elke, Umans, Victor A. W. M., de Maat, Moniek, Manintveld, Olivier C., Caliskan, Kadir, Constantinescu, Alina A., Mouthaan, Henk, Cornel, Jan-Hein, Baart, Sara, Akkerhuis, K. Martijn, Boersma, Eric, Kardys, Isabella
      Abstract: Objective This article investigates whether longitudinally measured fibrinolysis factors are associated with cardiac events in patients with chronic heart failure (CHF). Methods A median of 9 (interquartile range [IQR] 5–10) serial, tri-monthly blood samples per patient were prospectively collected in 263 CHF patients during a median follow-up of 2.2 (IQR 1.4–2.5) years. Seventy patients (cases) reached the composite endpoint of cardiac death, heart failure hospitalization, left ventricular assist device, or heart transplantation. From all longitudinal samples, we selected baseline samples in all patients and the last two samples before the event in cases or the last sample available in event-free patients. Herein, we measured plasminogen activator inhibitor 1 (PAI-1), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), and soluble urokinase plasminogen activator surface receptor (suPAR). Associations between temporal biomarker patterns during follow-up and the cardiac event were investigated using a joint model. Results Cases were on average older and showed higher New York Heart Association class than those who remained event-free. They also had lower blood pressures, and were more likely to have diabetes, renal failure, and atrial fibrillation. Longitudinally measured PAI-1, uPA, and suPAR were independently associated with adverse cardiac events after correction for clinical characteristics (hazard ratio [95% confidence interval]) per standard deviation increase of 2.09 (1.28–3.45) for PAI-1, 1.91 (1.18–3.24) for uPA, and 3.96 (2.48–6.63) for suPAR. Serial measurements of tPA were not significantly associated with the event after correction for multiple testing. Conclusion Longitudinally measured PAI-1, uPA, and suPAR are strongly associated with adverse cardiac events during the course of CHF. If future research confirms our results, these fibrinolytic factors may carry potential for improved, and personalized, heart failure surveillance and treatment monitoring.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-28T00:00:00+0100
      DOI: 10.1055/s-0039-1696973
       
  • Could Some Nonhemostatic Plasma Proteins Serve as Refuse Collectors for
           Fibrin(ogen)'
    • Thromb Haemost
      DOI: 10.1055/s-0039-1697619



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost ; : -2019-10-28T00:00:00+0100
       
  • Fibrin Clot Properties and Thrombin Generation in Hypertrophic
           Cardiomyopathy
    • Thromb Haemost
      DOI: 10.1055/s-0039-1697956



      Georg Thieme Verlag KG Stuttgart · New York

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      Thromb Haemost ; : -2019-10-28T00:00:00+0100
       
  • NOAC Adherence of Patients with Atrial Fibrillation in the Real World:
           Dosing Frequency Matters'
    • Authors: Hwang; Jongmin, Han, Seongwook, Bae, Han-Joon, Jun, Seung-Woon, Choi, Sang-Woong, Lee, Cheol-Hyun, Kim, In-Cheol, Cho, Yun-Kyeong, Park, Hyoung-Seob, Yoon, Hyuck-Jun, Kim, Hyungseop, Nam, Chang-Wook, Hur, Seung-Ho, Lee, Sang-Hoon
      Abstract: Background and Objectives Nonvitamin K antagonist oral anticoagulants (NOACs) require stricter medication adherence. We investigated the NOACs adherence in real-world practice. Methods We screened all patients in our cardiology department the day before their outpatient appointment, over a 5-month period. We enrolled 719 consecutive patients who were taking NOACs for atrial fibrillation. The patients were contacted by phone or text to bring the remnant pills with them without any information why. Adherence was measured by the percentage of prescribed doses taken (PDT) (number of doses taken/number of doses expected to be taken from the last prescription × 100 [%]) and the Morisky Medication Adherence Scale (MMAS)-8. Results All 4 NOACs (apixaban 47.8%, dabigatran 21.2%, rivaroxaban 18.4%, and edoxaban 12.6%) were prescribed. The mean duration that the patients had been taking NOACs was 7.2 ± 5.7 months. The PDT was 95.4 ± 9.1% in the once-daily dosing group and 93.4 ± 12.7% in the twice-daily group, and the difference was statistically significant (p = 0.017). The mean MMAS was 2.6 ± 0.8. The proportion of patients with a PDT 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-28T00:00:00+0100
      DOI: 10.1055/s-0039-1697954
       
  • Dietary Intake of Marine Polyunsaturated n-3 Fatty Acids and Risk of
           Recurrent Venous Thromboembolism
    • Authors: Isaksen; Trond, Evensen, Line H., Brækkan, Sigrid K., Hansen, John-Bjarne
      Abstract: Background Limited knowledge exists on the association between intake of long-chained n-3 polyunsaturated fatty acids (n-3 PUFAs) and risk of recurrence and all-cause mortality in patients with venous thromboembolism (VTE). Objectives This article investigates whether intake of marine n-3 PUFAs was associated with risk of recurrence and mortality in patients with incident VTE. Methods A total of 595 patients with incident VTE and available data on n-3 PUFA intake were derived from the Tromsø Study surveys 4 (1994–1995) and 6 (2007–2008). Weekly intake of n-3 PUFAs was categorized as low, medium, and high based on tertiles. Recurrent VTEs and all-cause mortality were registered up to December 31, 2016. Hazard ratios (HRs) were calculated using Cox regression models with the low intake category as reference. Results There were 98 recurrent VTEs and 227 deaths during follow-up. Overall, we found no association between intake of n-3 PUFAs and risk of recurrent VTE. However, inverse associations were found for high intakes in patients with unprovoked VTE (HR 0.45, 95% confidence interval [CI]: 0.20–1.01), cancer-free patients (HR 0.51, 95% CI: 0.27–0.95), and deep vein thrombosis (DVT) patients (HR 0.49, 95% CI: 0.24–0.97). The inverse associations were more evident when follow-up was restricted to the time after discontinuation of anticoagulant therapy. No association was observed between intake of n-3 PUFAs and mortality after incident VTE. Conclusion A high dietary intake of marine n-3 PUFAs was associated with lower risk of recurrent VTE after unprovoked index events, DVT, and in cancer-free patients.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-28T00:00:00+0100
      DOI: 10.1055/s-0039-1697663
       
  • Incidence of Stent Thrombosis after Endovascular Treatment of Iliofemoral
           or Caval Veins in Patients with the Postthrombotic Syndrome
    • Authors: Sebastian; Tim, Spirk, David, Engelberger, Rolf P., Dopheide, Jörn F., Baumann, Frederic A., Barco, Stefano, Spescha, Rebecca, Leeger, Claudia, Kucher, Nils
      Abstract: Background Patients with postthrombotic syndrome (PTS) treated with stents are at risk of stent thrombosis (ST). The incidence of ST in the presence and absence of anticoagulation therapy (AT) is unknown. Risk factors are not well understood. Patients and Methods From the prospective Swiss Venous Stent registry, we conducted a subgroup analysis of 136 consecutive patients with PTS. Incidence of ST was estimated from duplex ultrasound or venography, and reported for the time on and off AT. Baseline, procedural, and follow-up data were evaluated to identify factors associated with ST. Results Median follow-up was 20 (interquartile range [IQR] 9–40) months. AT was stopped in 43 (32%) patients after 12 (IQR 6–14) months. Cumulative incidence of ST was 13.7% (95% confidence interval [CI] 7.8–19.6%) and 21.2% (95% CI 13.2–29.2%) during the first 6 and 36 months, respectively. The time-adjusted incidence rate was 11.2 (95% CI 7.7–16.2) events per 100 patient-years, 11.3 (95% CI 7.3–17.3) for the period on, and 11.2 (95% CI 5.3–23.6) for the period off AT. May–Thurner syndrome (MTS) was associated with decreased incidence of ST (hazard ratio [HR] 0.37, 95% CI 0.15–0.91), whereas age 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-28T00:00:00+0100
      DOI: 10.1055/s-0039-1697955
       
  • A Thrombin-Activatable Factor X Variant Corrects Hemostasis in a Mouse
           Model for Hemophilia A
    • Authors: Muczynski; Vincent, Verhenne, Sebastien, Casari, Caterina, Chérel, Ghislaine, Panicot-Dubois, Laurence, Gueguen, Paul, Trossaert, Marc, Dubois, Christophe, Lenting, Peter J., Denis, Cécile V., Christophe, Olivier D.
      Abstract: Engineered recombinant factor X (FX) variants represent a promising strategy to bypass the tenase complex and restore hemostasis in hemophilia patients. Previously, a thrombin-activatable FX variant with fibrinopeptide-A replacing the activation peptide (FX-delAP/FpA) has been described in this regard. Here we show that FX-delAP/FpA is characterized by a sixfold shorter circulatory half-life compared with wild-type FX, limiting its therapeutical applicability. We therefore designed a variant in which the FpA sequence is inserted C-terminal to the FX activation peptide (FX/FpA). FX/FpA displayed a similar survival to wt-FX in clearance experiments and could be converted into FX by thrombin and other activating agents. In in vitro assays, FX/FpA efficiently restored thrombin generation in hemophilia A and hemophilia B plasmas, even in the presence of inhibitory antibodies. Expression following hydrodynamic gene transfer of FX/FpA restored thrombus formation in FVIII-deficient mice in a laser-induced injury model as well as hemostasis in a tail-clip bleeding model. Hemostasis after tail transection in FVIII-deficient mice was also corrected at 5 and 90 minutes after injection of purified FX/FpA. Our data indicate that FX/FpA represents a potential tenase-bypassing agent for the treatment of hemophilia patients with or without inhibitors.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-22T00:00:00+01:00
      DOI: 10.1055/s-0039-1697662
       
  • Blood Transfusion and Risk of Venous Thromboembolism: A Population-Based
           Cohort Study
    • Authors: Lin; Shih-Yi, Chang, Yun-Lung, Yeh, Hung-Chieh, Lin, Cheng-Li, Kao, Chia-Hung
      Abstract: Background The risk of venous thromboembolism (VTE) in generally ill patients, both under outpatient and inpatient care, following blood transfusion has not been determined. Methods This retrospective population-based cohort study was conducted using the National Health Insurance Research Database. We studied patients who received blood transfusion, defined as red blood cell transfusion of any type, from January 1, 2000 to December 31, 2011. The index date was defined as the date of blood transfusion. The primary outcome was VTE. Propensity score matching and Cox proportional hazard models were used. Results A total of 41,866 patients who underwent blood transfusion and 41,866 matched controls were studied. Generally, the blood transfusion cohort has 2.98 times higher risk of VTE than the control cohort (95% confidence interval [CI] = 1.23–7.22). The blood transfusion cohort had respectively 1.99 and 1.64 times higher risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) compared with the control cohort (DVT, 95% CI = 1.65–2.41; PE, 95% CI = 1.19–2.26). Patients in the blood transfusion cohort who did not use warfarin were 1.95 times more likely to develop VTE than those in the control cohort (adjusted hazard ratio [HR]: 1.95, 95% CI = 1.65–2.31). Patients in the blood transfusion cohort were 1.74 times more likely to die than those in the control cohort (adjusted HR: 1.74, 95% CI = 1.48–2.05). Conclusion Blood transfusion is associated with an increased risk of VTE. The risk of VTE decreased in those who took warfarin.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-22T00:00:00+01:00
      DOI: 10.1055/s-0039-1697664
       
  • A Synthetic Triple Helical Collagen Peptide as a New Agonist for Flow
           Cytometric Measurement of GPVI-Specific Platelet Activation
    • Authors: Sang; Yaqiu, Huskens, Dana, Wichapong, Kanin, de Laat, Bas, Nicolaes, Gerry A. F., Roest, Mark
      Abstract: Synthetic cross-linked collagen-related peptide (CRP-XL) is a glycoprotein VI (GPVI) receptor activator for platelet activation. This triple helical peptide, widely used in platelet function tests, is synthesized and cross-linked through cysteine residues at its N-terminus and C-terminus. Currently, there is only one laboratory, which is capable to produce this valuable peptide for clinical applications. In an attempt to provide a standardized alternative for CRP-XL, we developed a synthetic triple helical collagen peptide (STH-CP) with the same primary sequence as CRP-XL (GPC-(GPO)10-GPCG-amide)3, which was both on the C-terminus and on the N-terminus fixed on a scaffold with a binding side for each of the three peptides. The performance of STH-CP on platelet function was studied using flow cytometry and compared with CRP-XL. We found that platelet activation pattern in response to STH-CP and CRP-XL is similar, although the STH-CP requires sixfold higher concentrations to activate platelets to the same state. The intra-assay percent coefficient of variation of STH-CP and CRP-XL were both 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-21T00:00:00+01:00
      DOI: 10.1055/s-0039-1697660
       
  • Early Inhibition of P-Selectin/P-Selectin Glycoprotein Ligand-1 Reduces
           Intimal Hyperplasia in Murine Vein Grafts through Platelet Adhesion
    • Authors: Tseng; Chi-Nan, Chang, Ya-Ting, Yen, Cih-Yi, Lengquist, Mariette, Kronqvist, Malin, Eriksson, Einar E., Hedin, Ulf
      Abstract: Inflammatory processes contribute to intimal hyperplasia (IH) and long-term failure of vein grafts used in bypass surgery. Leukocyte recruitment on endothelial cells of vessels during inflammation is regulated by P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), which also mediates the interaction between platelets and endothelial cells in vein grafts transferred to arteries. However, how this pathway causes IH in vein grafts is unclear. In this study, we used a murine model of vein grafting to investigate P-selectin-mediated platelet adhesion, followed by IH. On the luminal surface of the vein graft, leukocyte recruitment occurred mainly in areas with adhered platelets rather than on endothelial cells without adherent platelets 1 hour after vein grafting. Blockage of either P-selectin or PSGL-1 reduced platelet adhesion and leukocyte recruitment on the luminal surface of vein grafts. Inhibition of the P-selectin pathway in vein grafts significantly reduced platelet-mediated leukocyte recruitment and IH of vein grafts 28 days after surgery. The study demonstrates that functional blockage of the P-selectin/PSGL-1 pathway in the early inflammatory phase after vein grafting reduced leukocyte invasion in the vein graft wall and later IH development. The findings imply an attractive early time window for prevention of vein graft failure by manipulating platelet adhesion.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-21T00:00:00+01:00
      DOI: 10.1055/s-0039-1697659
       
  • Upgrading Therapy Strategy Improves Pregnancy Outcome in Antiphospholipid
           Syndrome: A Cohort Management Study
    • Authors: Hoxha; Ariela, Favaro, Maria, Calligaro, Antonia, Del Ross, Teresa, Ruffatti, Alessandra Teresa, Infantolino, Chiara, Tonello, Marta, Mattia, Elena, Ruffatti, Amelia
      Abstract: The current study evaluates the efficacy and safety of different treatment strategies for pregnant patients with antiphospholipid syndrome. One hundred twenty-seven consecutive pregnancies were assessed; 87 (68.5%) with a history of pregnancy morbidity alone were treated with prophylactic low molecular weight heparin (LMWH) + low-dose aspirin (LDA, 100 mg) (group I) and 40 (31.5%) with a history of thrombosis and/or severe pregnancy complications with therapeutic LMWH + LDA (group II). LMWH doses were increased throughout the pregnancies depending on the patients' weight gain, and treatment was switched to a more intensive one at the first sign of maternal/fetal complications. The study's primary outcome was live births. There were no significant differences in live birth rate between group I (95.4%) and group II (87.5%). Even fetal complication rate was similar in the two groups; group II nevertheless had a higher prevalence of maternal and neonatal complications (p = 0.0005 and p = 0.01, respectively) and registered a significantly lower gestational age at delivery and birth weight (p = 0.0001 and p = 0.0005, respectively). Two patients in group I switched to group II therapy, six patients in group II switched to a more intensive treatment strategy (weekly plasma exchange + fortnightly intravenous immunoglobulins in addition to therapeutic LMWH + LDA). The multivariate analysis uncovered that triple antiphospholipid antibodies positivity was an independent factor leading to a more intensive therapy. All eight switched patients achieved a live birth. Study results revealed that adjusted LMWH doses and switching therapy at first signs of severe pregnancy complications led to a high rate of live births in antiphospholipid syndrome patients.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-21T00:00:00+01:00
      DOI: 10.1055/s-0039-1697665
       
  • Prophylaxis of Venous Thromboembolism after Hospital Discharge in Internal
           Medicine: Findings from the Observational FADOI-NoTEVole Study
    • Authors: Squizzato; Alessandro, Agnelli, Giancarlo, Campanini, Mauro, Dentali, Francesco, Agnelli, Francesca, Bonizzoni, Erminio, Franco, Alessandro, Gallo, Andrea, Gussoni, Gualberto, Nitti, Cinzia, Triolo, Giuseppa, Valerio, Antonella, Ventrella, Francesco, Fontanella, Andrea
      Abstract: Background and Aim Post-discharge prophylaxis for venous thromboembolism (VTE) is a challenging issue in patients hospitalised in Internal Medicine Units (IMUs). The aim of this study was to evaluate the frequency and the factors associated with post-discharge prophylaxis for VTE in IMUs. Methods Multi-centre, retrospective study including consecutive patients who were admitted for any cause and discharged from an IMU. Results Overall, 3,740 patients (mean age 74.1 ± 15.7 years) were included in the study at 38 IMUs in Italy. At discharge, the percentage of patients receiving pharmacological thromboprophylaxis was 16.0% (20.1% after excluding patients treated with anticoagulants for indications other than VTE prophylaxis). At multivariable analysis, history of ischaemic stroke, hypomobility ≥ 7 days, central venous catheter, ≥ 10 versus ≤ 5 days of hospital stay, use of corticosteroids, cancer, history of falls, availability of a caregiver, infections and age were significantly associated with thromboprophylaxis, while an inverse correlation was observed with concomitant anti-platelet drugs and platelet count 
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-21T00:00:00+01:00
      DOI: 10.1055/s-0039-1697661
       
  • Rapid Centrifugation in the Routine Hemostasis Laboratory
    • Authors: Wolfensberger; Nathan, Georgiou, Georgios, Giabbani, Evelyne, Reusser, Marianne, Njue, Linet M., Fiedler, Martin, Leichtle, Alexander B., Nagler, Michael
      Abstract: Background The use of short and uniform centrifugation schemes contributes significantly to the successful automation of laboratory procedures. It is however unclear if this is applicable to the hemostasis laboratory. Objectives This article assesses the accuracy of measurements obtained with a rapid, high-speed centrifugation scheme in a large set of hemostasis tests, covering the full spectrum of values obtained in clinical practice, and using meaningful statistical measures. Methods Two citrated plasma samples were obtained from consecutive patients of a tertiary hospital with suspected abnormal hemostasis tests and processed with two centrifugation schemes in parallel: 1,500 × g for 10 minutes and 3,137 × g for 7 minutes. The following tests were conducted: prothrombin time (n = 125), international normalized ratio (n = 146), activated partial thromboplastin time (n = 119), thrombin time (n = 105), fibrinogen (n = 125), factor (F)II (n = 69), FV (n = 64), FVII (n = 64), FX (n = 67), FVIII (n = 55), FIX (n = 37), FXI (n = 35), and FXIII (n = 20), D-dimer (n = 34), antithrombin (n = 31), anti-Xa activity (n = 30), von Willebrand antigen (n = 25), and von Willebrand activity (VWF:GPIbM; n = 27). Results A wide range of results were obtained in all tests. Spearman's rank correlation coefficient was at least 0.95 for all tests except FV, FIX, and FXI. The coverage probability π at a given deviation index κ of 15% was above 0.9 for all tests except FV, FVII, FX, FVIII, FIX, FXI, and VWF:GPIbM, suggesting a lack of agreement. Conclusion Our results suggest that high-speed centrifugation is applicable to the majority of routine hemostasis parameters. The coverage probability was more sensitive than Spearman's rank correlation to detect disagreement among centrifugation schemes.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-10T00:00:00+01:00
      DOI: 10.1055/s-0039-1696712
       
  • Effectiveness and Safety of Primary Thromboprophylaxis in Children with
           Cancer: A Systematic Review of the Literature and Network Meta-Analysis
    • Authors: Pelland-Marcotte; Marie-Claude, Tole, Soumitra, Pechlivanoglou, Petros, Brandão, Leonardo Rodrigues
      Abstract: Thromboembolism (TE) is a well-recognized complication of pediatric cancer and can lead to mortality and excess morbidity. There is conflicting evidence about the effectiveness and safety of thromboprophylaxis in children. We conducted a systematic literature review and network meta-analysis of primary pharmacological thromboprophylaxis in children and adolescents (0–21 years) with cancer. The primary outcomes were objectively proven TE and major bleeding. The network meta-analysis included comparisons of multiple alternatives simultaneously: antithrombin (AT) replacement, low molecular weight heparin (LMWH), vitamin K antagonists (VKAs), and standard of care (SOC) defined as no thromboprophylaxis or low-dose heparin for catheter patency. Six articles describing 1,318 patients were included (mean age: 6.7 years, 56.7% male). Acute lymphoblastic leukemia was the underlying diagnosis in 97.5% of patients. All studies were considered at moderate or high risk of bias. LMWH was the only agent associated with lower odds of TE compared with SOC (odds ratio [OR]: 0.23, 95% confidence interval [CI]: 0.06–0.81). No statistically significant difference was detected between other thromboprophylaxis modalities and SOC. Tau2 and I 2 suggested a high degree of heterogeneity. No statistically significant differences in the odds of major bleeding were found between AT replacement, LMWH, VKA, and SOC. Current evidence suggests that low-dose LMWH is effective and safe to prevent TE in children with cancer but is insufficient to conclude if AT replacement or VKA are effective thromboprophylaxis options. Further research, notably randomized controlled trials enrolling children with diverse types of cancer, is crucially needed.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-10T00:00:00+01:00
      DOI: 10.1055/s-0039-1697027
       
  • Premorbid Hemostasis in Women with a History of Pregnancy Loss
    • Authors: Peshkova; Alina D., Safiullina, Svetlana I., Evtugina, Natalia G., Baras, Yelena S., Ataullakhanov, Fazoil I., Weisel, John W., Litvinov, Rustem I.
      Abstract: Background Congenital and acquired hemostatic disorders are among the pathogenic factors of pregnancy loss. Studying mechanistic relations between impaired hemostasis and fetal losses is important for the prognosis and prophylaxis of obstetric complications. Objective This article aims to establish latent hemostatic disorders in nonpregnant women as an important premorbid risk factor of pregnancy loss. Methods and Results Hemostasis was characterized using two relatively new in vitro assays, namely thrombodynamics (spatial clot growth) and kinetics of blood clot contraction, which together reflect the hemostatic or thrombotic potential. In addition, platelet functionality was assessed using flow cytometry. Our study included 50 women with a history of pregnancy loss and 30 parous women without previous obstetric complications. In patients with pregnancy loss, hypercoagulability was observed along with significant impairment of blood clot contraction associated with chronic platelet activation and dysfunction. Both hypercoagulability and defective clot contraction were significantly more pronounced in patients with a history of three or more miscarriages compared with patients with a history of one or two miscarriages. In addition, a significant inhibition of clot contraction was found in patients with miscarriage occurring after 10 weeks of gestation compared with those who lost a fetus earlier in pregnancy. Conclusion These results indicate that chronic hypercoagulability and impaired clot contraction constitute a premorbid status in patients with pregnancy loss. The data confirm a significant pathogenic role of hemostatic disorders in pregnancy loss and suggest the predictive value of thrombodynamics and blood clot contraction assays in evaluating the risk of pregnancy loss.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-06T00:00:00+01:00
      DOI: 10.1055/s-0039-1696972
       
  • Prevalence of Antiphospholipid Antibodies Negativisation in Patients with
           Antiphospholipid Syndrome: A Long-Term Follow-Up Multicentre Study
    • Authors: Radin; Massimo, Schreiber, Karen, Sciascia, Savino, Roccatello, Dario, Cecchi, Irene, Aguirre Zamorano, María Ángeles , Cuadrado, Maria Jose
      Abstract: Objective This article aims to analyse the rate of antiphospholipid antibodies (aPL) negativisation in patients with antiphospholipid syndrome (APS), and to evaluate potential new clinical manifestations after negativisation and/or aPL fluctuations in a long-term follow-up. Methods Inclusion criteria are (1) any patients with an APS diagnosis according to the current Sydney criteria and (2) patients in whom aPL negativisation occurred. aPL negativisation was defined as repeated aPL measurements on at least two consecutive occasions at least 12 weeks apart, with a follow-up of at least 1 year since aPL first turned negative. Results Out of 259 APS patients, a total of 23 patients (8.9%) met the inclusion criteria for persistent aPL negativisation. Patients were followed-up for 14.4 ± 8.1 years, experienced aPL negativisation after a mean of 5.3 ± 3.5 years and were followed-up after experiencing the aPL negativisation for a mean of 7.6 ± 5.8 years. Seventeen patients (73.9%) presented with thrombotic APS, 2 with pregnancy morbidity (8.7%) and 4 (17.4%) with both. Most of the patients (18; 78.3%) had a single aPL positivity, 5 (21.7%) double, while no triple aPL positivity was observed. At the time of data collection, after aPL negativisation, anticoagulation was stopped in 8 patients with previous thrombotic venous event (8/21, 38%) according to the treating physicians' judgements. None of the patients experienced any recurrent thrombotic event during the follow-up period after their aPL negativisation. Conclusion In our patient cohort consisting of 259 patients with definitive APS, we observed over a mean observation period of > 5 years, that aPL negativisation occurred in approximately 9% of patients. Negativisation occurred most often in patients who were previously found to be positive for only one aPL.
      Citation: Thromb Haemost ; : -
      PubDate: 2019-10-06T00:00:00+01:00
      DOI: 10.1055/s-0039-1696687
       
  • 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
       
  • 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
       
  • 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

      Artikel in Thieme eJournals:
      Inhaltsverzeichnis     Volltext

      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

      Artikel in Thieme eJournals:
      Inhaltsverzeichnis     Volltext

      Thromb Haemost ; : -2019-08-30T00:00:00+01:00
       
 
 
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