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Journal Cover Thrombosis & Haemostasis
  [SJR: 2.089]   [H-I: 162]   [119 followers]  Follow
   Partially Free Journal Partially Free Journal
   ISSN (Print) 0340-6245
   Published by Schattauer Publishers Homepage  [1 journal]
  • Ahead of print: Clinical Decision Rules for Pulmonary Embolism in
           Hospitalized Patients: A...
    • Authors: A. Bass (1; 2, K. G. Fields (3, R. Goto (4, G. Turissini (1, S. Dey (1, L. A. Russell (1, 2
      Abstract: Background Clinical decision rules (CDRs) for pulmonary embolism (PE) have been validated in outpatients, but their performance in hospitalized patients is not well characterized. Objectives The goal of this systematic literature review was to assess the performance of CDRs for PE in hospitalized patients. Methods We performed a structured literature search using Medline, EMBASE and the Cochrane library for articles published on or before January 18, 2017. Two authors reviewed all titles, abstracts and full texts. We selected prospective studies of symptomatic hospitalized patients in which a CDR was used to estimate the likelihood of PE. The diagnosis of PE had to be confirmed using an accepted reference standard. Data on hospitalized patients were solicited from authors of studies in mixed populations of outpatients and hospitalized patients. Study characteristics, PE prevalence and CDR performance were extracted. The methodological quality of the studies was assessed using the QUADAS instrument. Results Twelve studies encompassing 3,942 hospitalized patients were included. Studies varied in methodology (randomized controlled trials and observational studies) and reference standards used. The pooled sensitivity of the modified Wells rule (cut-off ≤ 4) in hospitalized patients was 72.1% (95% confidence interval [CI], 63.7–79.2) and the pooled specificity was 62.2% (95% CI, 52.6–70.9). The modified Wells rule (cut-off ≤ 4) plus D-dimer testing had a pooled sensitivity 99.7% (95% CI, 96.7–100) and pooled specificity 10.8% (95% CI, 6.7–16.9). The efficiency (proportion of patients stratified into the ‘PE unlikely’ group) was 8.4% (95% CI, 4.1–16.5), and the failure rate (proportion of low likelihood patients who were diagnosed with PE during follow-up) was 0.1% (95% CI, 0–5.3). Conclusion In symptomatic hospitalized patients, use of the Wells rule plus D-dimer to rule out PE is safe, but allows very few patients to forgo imaging....
      PubDate: 2017-10-10 15:40:54
  • Ahead of print: Down Regulation of the Munc18b-syntaxin-11 Complex and
           β1-tubulin Impairs Secretion...
    • Authors: E. Caparrós-Pérez (1; R. Teruel-Montoya (1, 2, V. Palma-Barquero (1, 2, J. M. Torregrosa (1, J. E. Blanco (3, J. L. Delgado (3, M. L. Lozano (1, 2, V. Vicente (1, 2, M. Sola-Visner (4, J. Rivera (1, 2, C. Martínez (1, F. Ferrer-Marín (2, 5
      Abstract: Neonatal platelets are hyporeactive and show impaired agonist-induced secretion despite no obvious abnormalities in their granules. Here, we examined, for the first time, the ultrastructure of neonatal and adult platelets following agonist activation. Under resting conditions, neonatal and adult platelets appeared ultrastructurally identical. Following agonist stimulation, however, noticeable degranulation occurred in adult platelets, while granules in neonatal platelets remained clearly visible and apparently unable to centralize or fuse. To investigate the underlying mechanisms, we first examined the expression levels of the main SNARE proteins, which mediate the membrane fusion events required for exocytosis. Neonatal platelets showed significantly reduced levels of syntaxin-11 and its regulator, Munc18b. Since granule centralization depends on contraction of the microtubule ring, we also examined the expression of its main component, β1-tubulin. Noteworthy, we found decreased TUBB1 mRNA and protein levels in neonatal platelets, while TUBB2A and TUBB isoforms were overexpressed, partially compensating for that deficiency. Finally, supporting the functional consequences of defective exocytosis, adhesion kinetic assays, performed in plasma-free medium, demonstrated delayed adhesion and spreading of neonatal platelets. This is the first report showing marked reductions of syntaxin-11–Munc18b complex and β1-tubulin in neonatal platelets, indicating that these proteins, required for platelet degranulation, are developmentally regulated....
      PubDate: 2017-10-10 15:30:57
  • Ahead of print: The Performance of CRUSADE and ACUITY Bleeding Risk Scores
           in Ticagrelor-Treated ACS...
    • Authors: S. Xi (1; S. Zhou (1, X. Wang (1, J. Liu (1, L. Qin (1, J. Liu (1, T. Yin (1, Y. Chen (1
      Abstract: The performance of the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) and ACUITY (Acute Catheterization and Urgent Intervention Triage strategy) risk scores for the prediction of major bleeding in ticagrelor-treated acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention (PCI) is unknown. The aim of the present study is to validate the performance of both scores in a contemporary Chinese cohort of ACS patients hospitalized for PCI and administrated with ticagrelor. From January 2013 to December 2014, a total of 629 ticagrelor-treated ACS patients who underwent PCI were recruited consecutively. The overall rate of major bleeding defined by the BARC (Bleeding Academic Research Consortium) criteria was 1.7%. This incidence increased with the risk category of both the CRUSADE (very low, 0.6%; low, 1.3%; moderate, 1.1%; high, 7.0%; and very high, 13.0%; p = 0.001) and the ACUITY score (low, 0.6%; moderate, 1.4%; high, 4.9%; and very high, 7.0%; p = 0.003). The CRUSADE score demonstrated adequate calibration and discriminatory capacity for the patients as a whole (HL-p [Hosmer–Lemeshow goodness-of-fit test p-value] >0.3; AUC [area under the curve]: 0.78), with the excellent performance in the subgroups of acute myocardial infarction, men, diabetes and those implanted with more than two DESs (AUC: 0.85, 0.80, 0.93 and 0.93, respectively). For the ACUITY score, adequate calibration and discriminatory capacity could be observed for the whole patients (HL-p > 0.3; AUC: 0.78), with excellent performance for the patients with diabetes or those implanted with more than two DESs (AUC: 0.90 and 0.97, respectively). In conclusion, both CRUSADE and ACUITY risk scores performed adequate discriminatory power for the prediction of major bleeding within 30 days in ticagrelor-treated ACS patients who underwent PCI....
      PubDate: 2017-10-10 15:21:39
  • Ahead of print: Serum Levels of Anti-PON1 and Anti-HDL Antibodies as
           Potential Biomarkers of...
    • Authors: P. López (1; J. Rodríguez-Carrio (1, A. Martínez-Zapico (2, A. I. Pérez-Álvarez (3, R. López-Mejías (4, L. Benavente (3, L. Mozo (5, L. Caminal-Montero (2, M. A. González-Gay (4, 6, 7, A. Suárez (1
      Abstract: The present study aimed to evaluate the possible role of immunoglobulin G (IgG) antibodies against high-density lipoproteins (HDL) and paraoxonase 1 (PON1) as possible biomarkers of cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). To this end, levels of these autoantibodies, PON1 activity and total antioxidant capacity were quantified in serum samples from 198 SLE patients, 100 healthy controls (HC) and 42 non-autoimmune individuals with traditional cardiovascular risk factors. PON1 rs662 polymorphism was analysed in a subgroup of patients and controls. Subclinical CVD were determined by Doppler ultrasound in 118 SLE patients and 30 HC, analysing carotid intima-media thickness (IMT) and blood flow parameters in internal carotid, middle cerebral and basilar arteries. Serum levels of both anti-HDL and anti-PON1 antibodies were increased in SLE patients compared with HC (p < 0.001); however, only anti-PON1 antibodies, in addition to disease activity, were significant predictors of the impaired PON1 function in SLE (β= 0.143, p = 0.045). Conversely, anti-HDL antibodies were associated with higher risk of CVD (odds ratio: 3.69; p = 0.012) and lower HDL levels at disease onset (ρ = 0.324, p = 0.044). Finally, anti-PON1 antibodies were associated with carotid IMT in SLE (β = 0.201, p = 0.008) and inversely related to cranial arteries blood flow velocities in patients with clinical and subclinical CVD (all p < 0.001). In sum, these findings allowed us to propose serum levels of anti-PON1 and anti-HDL antibodies as potential early biomarkers of endothelial damage and premature atherosclerosis in SLE, thus constituting useful therapeutic targets for the prevention of future CVD in these patients....
      PubDate: 2017-10-10 15:20:17
  • Ahead of print: Investigation of the Filamin A–Dependent Mechanisms of
           Tissue Factor Incorporation...
    • Authors: M. Collier (1; M. E. W. Collier (2, C. Ettelaie (3, B. T. Goult (4, A. Maraveyas (5, A. H. Goodall (2
      Abstract: We have previously shown that phosphorylation of tissue factor (TF) at Ser253 increases the incorporation of TF into microvesicles (MVs) following protease-activated receptor 2 (PAR2) activation through a process involving filamin A, whereas phosphorylation of TF at Ser258 suppresses this process. Here, we examined the contribution of the individual phosphorylation of these serine residues to the interaction between filamin A and TF, and further examined how filamin A regulates the incorporation of TF into MVs. In vitro binding assays using recombinant filamin A C-terminal repeats 22–24 with biotinylated phospho-TF cytoplasmic domain peptides as bait showed that filamin A had the highest binding affinities for phospho-Ser253 and double-phosphorylated TF peptides, while the phospho-Ser258 TF peptide had the lowest affinity. Analysis of MDA-MB-231 cells using an in situ proximity ligation assay revealed increased proximity between the C-terminus of filamin A and TF following PAR2 activation, which was concurrent with Ser253 phosphorylation and TF-positive MV release from these cells. Knock-down of filamin A expression suppressed PAR2-mediated increases in cell surface TF procoagulant activity without reducing cell surface TF antigen expression. Disrupting lipid rafts by pre-incubation with methyl-β-cyclodextrin prior to PAR2 activation reduced TF-positive MV release and cell surface TF procoagulant activity to the same extent as filamin A knock-down. In conclusion, this study shows that the interaction between TF and filamin A is dependent on the differential phosphorylation of Ser253 and Ser258. Furthermore, the interaction of TF with filamin A may translocate cell surface TF to cholesterol-rich lipid rafts, increasing cell surface TF activity as well as TF incorporation and release into MVs....
      PubDate: 2017-10-10 15:11:42
  • Ahead of print: Preprocedural Leucocyte Count Predicts Risk in Patients
           with Coronary Chronic Total...
    • Authors: C. Gebhard (1; A. Toma (1, Z. Min (1, B. E. St&auml;hli (2, K. Mashayekhi (1, M. Gick (1, M. Ferenc (1, H. B&uuml;ttner (1, F.-J. Neumann (1
      Abstract: Background As technologies of percutaneous coronary intervention (PCI) for coronary chronic total occlusions (CTO) have improved, great uncertainty exists regarding patient selection and long-term benefit of CTO-PCI. Given that white blood cell (WBC) count has been associated with cardiovascular risk, we hypothesized that the latter might provide incremental prognostic value in patients undergoing CTO-PCI. Methods and Results Our study population consisted of 1,262 consecutive patients (76.3% males, mean age of 67.7 ± 10.3 years) who underwent elective PCI at our centre between January 2002 and December 2008. Four hundred seventy-five patients had at least one CTO, while 787 patients with non-occlusive coronary lesions served as controls. Baseline WBC count was higher in CTO patients as compared with controls (8,072 ± 3,459/μL vs. 7,469 c 2,668/μL, p = 0.001) and independently predicted the occurrence of a CTO lesion (odds ratio: 1.8; 95% confidence interval [CI]: 1.3–2.4; p < 0.001). After a median follow-up of 3.1 years (interquartile range: 2.1–4.2 years), CTO patients with WBC counts ranging in the highest tertile had significantly worse outcomes than CTO patients with lower WBC counts (log-rank = 0.009 for all-cause mortality and log-rank = 0.01 for major adverse cardiac events). These associations were not seen in controls. Accordingly, elevated WBC count was identified as a significant predictor for all-cause mortality (adjusted hazard ratio: 3.1; 95% CI: 1.6–6.2; p = 0.001) in CTO patients but not in patients with non-occlusive coronary artery disease (pint = 0.088). Conclusion Assessment of the inflammatory status of CTO patients may be an important element in selecting CTO patients at low risk who may be referred to CTO-PCI....
      PubDate: 2017-10-10 15:08:15
  • Ahead of print: Mitochondria and Platelet Cell Death
    • Authors: A. Kholmukhamedov (1; S. Jobe (1
      PubDate: 2017-10-10 15:03:21
  • Ahead of print: Protease-Activated Receptor PAR-4: An Inducible Switch
           between Thrombosis and...
    • Authors: A. C. Fender (1; 2, B. H. Rauch (3, T. Geisler (4, K. Schr&ouml;r (1
      Abstract: Thrombin triggers activation of platelets through protease-activated receptor 1 (PAR-1) and PAR-4. Both receptors are widely expressed and exert multiple platelet-independent functions. PAR signalling contributes to healing responses after injury, by promoting cytokine activity and cellular growth and mobility. Uncontrolled PAR activation, however, can prevent timely resolution of inflammation, enhance thrombogenic endothelial function and drive adverse remodelling. The specific role of PAR-4 in thromboinflammatory vascular disease has been largely underestimated, given the relatively limited expression of PAR-4 in non-platelet cells under healthy conditions. However, unlike PAR-1, PAR-4 expression adapts dynamically to numerous stimuli associated with thromboinflammation, including thrombin, angiotensin II, sphingosine-1-phosphate (S1P), high glucose and redox stress, suggesting expression is switched on ‘at need’. Prostacyclin negatively regulates PAR-4 expression at the post-transcriptional level, which may serve to fine-tune thrombin responses and limit these to the injury site. PAR-4 elicits inflammatory, mitogenic and proliferative actions not only in response to thrombin but also to numerous other inflammatory proteases, and can cross-talk with other receptor systems such as S1P and adenosine receptors. Accordingly, PAR-4 has emerged as a candidate player in vessel disease and cardiac post-infarction remodelling. Currently, PAR-4 is a particularly promising target for safer anti-thrombotic therapies. Recent studies with the PAR-4 antagonist BMS-986120 lend support to the concept that selective antagonism of PAR-4 may offer both an effective and safe anti-thrombotic therapy in the acute thrombotic setting as well as an anti-inflammatory strategy to prevent long-term progressive atherosclerotic disease in high-risk cardiovascular patients....
      PubDate: 2017-10-10 15:02:34
  • Ahead of print: Open Access: Nebulized Heparin Attenuates Pulmonary
           Coagulopathy and Inflammation...
    • Authors: L. Chimenti (1); M. Camprub&iacute;-Rimblas (1, 2), R. Guillamat-Prats (1, 3), M. N. Gomez (1), J. Tijero (1), L. Blanch (1, 2, 3, 4), A. Artigas (1, 2, 3, 4)
      Abstract: Objective▓Alveolar macrophages play a key role in the development and resolution of acute respiratory distress syndrome (ARDS), modulating the inflammatory response and the coagulation cascade in lungs. Anti-coagulants may be helpful in the treatment of ARDS. This study investigated the effects of nebulized heparin on the role of alveolar macrophages in limiting lung coagulation and inflammatory response in an animal model of acute lung injury (ALI). Methods▓Rats were randomized to four experimental groups. In three groups, ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) and heparin was nebulized at constant oxygen flow: the LPS/Hep group received nebulized heparin 4 and 8 hours after injury; the Hep/LPS/Hep group received nebulized heparin 30 minutes before and 4 and 8 hours after LPS-induced injury; the LPS/Sal group received nebulized saline 4 and 8 hours after injury. The control group received only saline. Animals were exsanguinated 24 hours after LPS instillation. Lung tissue, bronchoalveolar lavage fluid (BALF) and alveolar macrophages isolated from BALF were analysed. Results▓LPS increased protein concentration, oedema and neutrophils in BALF as well as procoagulant and proinflammatory mediators in lung tissue and alveolar macrophages. In lung tissue, nebulized heparin attenuated ALI through decreasing procoagulant (tissue factor, thrombin–anti-thrombin complexes, fibrin degradation products) and proinflammatory (interleukin 6, tumour necrosis factor alpha) pathways. In alveolar macrophages, nebulized heparin reduced expression of procoagulant genes and the effectors of transforming growth factor beta (Smad 2, Smad 3) and nuclear factor kappa B (p-selectin, CCL-2). Pre-treatment resulted in more pronounced attenuation. Conclusion▓Nebulized heparin reduced pulmonary coagulopathy and inflammation without producing systemic bleeding, partly by modulating alveolar macrophages....
      PubDate: 2017-10-04 16:07:02
  • Ahead of print: Platelets Contribute to the Accumulation of Matrix
           Metalloproteinase Type 2 in...
    • Authors: A. Alunno (1); E. Falcinelli (2), F. Luccioli (1), E. Petito, E. Bartoloni (1), S. Momi (2), G. Mirabelli (1), G. B. Mancini (3), R. Gerli (1), P. Gresele (1, 2)
      Abstract: Inflammation plays a role in the initiation and progression of osteoarthritis (OA), a chronic degenerative joint disorder. Platelets are inflammatory cells, contain and release matrix metalloproteinases (MMPs) and favour the release of these enzymes, key effectors of cartilage and subchondral bone degradation, by other cells; however, their role in OA has not been investigated yet. Our aims were (1) to assess the presence of platelets and of MMP-2 in synovial fluid (SF) of OA patients; (2) to evaluate the contribution of platelets to MMP-2 release by fibroblast-like synoviocytes (FLS); and (3) to investigate if hyaluronic acid (HA) interferes with these processes. SF was collected from 27 OA patients before and after treatment with intra-articular HA (20 mg/2 mL). Moreover, FLS were co-cultured with platelets, and the release of MMP-2 in supernatants was measured. Our results show that platelets are present in OA SF and show markers of activation. OA SF also contains relevant amounts of MMP-2. Co-incubation of platelets with FLS favours the release of MMP-2 by the interaction of platelet surface P-selectin with FLS CD44 by a mechanism involving the activation of pAkt and pSrc in FLS. Administration of HA to OA patients decreased the infiltration of platelets in SF and reduced the levels of MMP-2. The addition of HA in vitro inhibited the release of MMP-2 by FLS triggered by the interaction with platelets. In conclusion, our data show that platelets may contribute to joint degeneration in OA by favouring the accumulation of MMP-2 in SF....
      PubDate: 2017-10-04 16:05:11
  • Ahead of print: Increasing Incidence and Recurrence Rate of Venous
           Thromboembolism in Paediatric...
    • Authors: C. Van Ommen (1); I. L. M. Klaassen (2, 3), A. L. van Els (2, 4), M. D. van de Wetering (4), C. H. Van Ommen (5)
      Abstract: Venous thromboembolism (VTE) is a serious complication in paediatric oncology patients. To identify the incidence, risk factors and recurrence rate of VTE in paediatric oncology patients, an observational, retrospective cohort study of all consecutive children (≦18 years) with malignancies, treated at the Emma Children’s Hospital Academic Medical Centre between January 1989 and December 2013, was done. A matched case–control study in children with lymphomas was performed, to identify thrombotic risk factors. Cumulative recurrence-free survival after first VTE was estimated by the Kaplan–Meier method. Of the 2,183 children included (male: female = 1.4:1.0; median age, 6.6 years) with cancer, 78 patients developed VTE (3.6%; 95% confidence interval [CI], 2.8–4.4). The incidence increased from 0.8% (4/478, 95% CI, 0.0–1.6) between 1989 and 1993 to 10.4% (44/423, 95% CI, 7.6–13.4) between 2009 and 2013. Independent risk factors for VTE were age ≥ 12 years, acute lymphoblastic leukaemia (ALL) and lymphoma. The case–control study in lymphoma patients showed a trend for increased VTE incidence in stage IV lymphoma. Twelve (15.4%) patients developed recurrent thrombosis, 7 patients while on therapeutic or prophylactic anticoagulation. The cumulative recurrence-free survival after first VTE was 88.5, 87.1 and 80.6% after 1, 5 and 10 years, respectively. In conclusion, we demonstrated an increasing incidence of VTE in children with malignancies, with age ≥ 12 years, ALL and lymphoma as independent risk factors. The elevated recurrence rate underlines the importance of full anticoagulant therapy and might warrant prophylactic anticoagulation after first VTE during cancer treatment....
      PubDate: 2017-10-04 16:02:50
  • Ahead of print: Dabigatran versus Warfarin for Acute Venous
           Thromboembolism in Elderly or Impaired...
    • Authors: S. Z. Goldhaber (1); S. Schulman (2), H. Eriksson (3), M. Feuring (4), M. Fraessdorf (4), J. Kreuzer (4), E. Sch&uuml;ler (5), S. Schellong (6), A. K. Kakkar (7)
      Abstract: Management of acute venous thromboembolism (VTE) with anticoagulants in elderly patients and those with chronic kidney disease poses special challenges. The RE-COVER and RE-COVER II trials showed that dabigatran 150 mg twice daily was as effective as warfarin over 6 months in preventing recurrent VTE, with a lower bleeding risk. We now assess the effects of old age and renal impairment (RI) on pooled trial outcomes in 5,107 patients: 4,504 aged <75 years and 603 aged ≥75 years. The primary efficacy outcome was symptomatic VTE/VTE-related death. Safety outcomes were centrally adjudicated major bleeding events (MBEs), MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs) and any bleeds. Baseline renal function was categorized as normal, mild RI or moderate RI. A total of 3,698 had normal renal function and 1,100 and 237 had mild and moderate RI, respectively (23 patients with severe RI and 49 with missing creatinine clearance data were not included). For dabigatran, VTE/VTE-related death decreased from 3.1% (normal renal function) to 1.9% for mild RI and to 0.0% for moderate RI. For warfarin, the event rates were 2.6, 1.6 and 4.1%, respectively. Overall, major bleeding increased with increasing RI (p = 0.0037) and with age (p = 0.4350), with no apparent difference between the dabigatran and warfarin patients. Dabigatran shows better efficacy than warfarin in RI and in the elderly patients, probably because of an increase in the concentration of dabigatran. However, bleeding risk increases with both dabigatran and warfarin in the presence of RI....
      PubDate: 2017-10-04 15:57:08
  • Ahead of print: Apixaban Auto-intoxication: Toxicokinetics and Coagulation
    • Authors: L. Mast (1); R. J. Verheul (1, 2), R. Reijnen (1), R. C. J. M. van Rossen (3), J. W. P. M. Overdiek (1), E. B. Wilms (3)
      PubDate: 2017-10-04 15:55:32
  • Ahead of print: Extracellular Cyclophilin A Augments Platelet-Dependent
           Thrombosis and...
    • Authors: S. N. I. v. Ungern-Sternberg (1); S. Vogel (1), B. Walker-Allgaier (1), S. Geue (1), A. Maurer (2), A. M. Wild (2), P. M&uuml;nzer (1), M. Chatterjee (1), D. Heinzmann (1), E. Kremmer (3), O. Borst (1), P. Loughran (4, 5), A. Zernecke (6), M. D. Neal (4), T. R. Billiar (4), M. Gawaz (1), P. Seizer (1)
      Abstract: Cyclophilin A (CyPA) is involved in the pathophysiology of several inflammatory and cardiovascular diseases. To our knowledge, there is no specific inhibitor targeting extracellular CyPA without affecting other extracellular cyclophilins or intracellular CyPA functions. In this study, we developed an antibody-based inhibitor of extracellular CyPA and analysed its effects in vitro and in vivo. To generate a specific antibody, mice and rats were immunized with a peptide containing the extracellular matrix metalloproteinase inducer binding site and various antibody clones were selected and purified. At first, antibodies were tested for their binding capacity to recombinant CyPA and their functional activity. The clone 8H7-mAb was chosen for further experiments. 8H7-mAb reduced the CyPA-induced migration of inflammatory cells in vitro and in vivo. Furthermore, 8H7-mAb revealed strong antithrombotic effects by inhibiting CyPA-dependent activation of platelets and thrombus formation in vitro and in vivo. Surprisingly, 8H7-mAb did not influence in vivo tail bleeding time or in vitro whole blood coagulation parameters. Our study provides first evidence that antibody-based inhibition of extracellular CyPA inhibits thrombosis and thromboinflammation without affecting blood homeostasis. Thus, 8H7-mAb may be a promising compound for thrombi modulation in inflammatory diseases to prevent organ dysfunction....
      PubDate: 2017-10-04 15:27:36
  • Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe
           Chronic Kidney Disease
    • Authors: M. Midei (1); D. Albrecht, M. P. Turakhia, D. Ries, T. Marbury, W. Smith, D. Dillon, P. G. Milner, M. G. Midei
      Abstract: Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin’s inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy....
      PubDate: 2017-09-21 15:14:03
  • Ahead of print: Detection of atrial fibrillation in patients with embolic
           stroke of undetermined...
    • Authors: C. Israel (1); A. Kitsiou (2), M. Kalyani (1), S. Deelawar (1), L. E. Ejangue (1), A. Rogalewski (2), C. Hagemeister (2), J. Minnerup (3), W. R. Sch&auml;bitz (2)
      Abstract: Recently, the clinical entity embolic stroke of undetermined source (ESUS) has been defined for patients with ischemic strokes, where neither a cardioembolic nor a non-cardiac source can be detected. These patients may suffer from asymptomatic atrial fibrillation (AF), terminating spontaneously and thus eluding detection. Implantable loop recorders (ILR) with automatic AF detection algorithms can detect short-lasting, subclinical AF. The aim of this study was to prospectively assess and predict AF detection in patients with ESUS using ILR with daily remote interrogation. Patients with acute ESUS received an ILR, were seen every 6 months and additionally interrogated their ILR daily using remote monitoring. The incidence of AF detection was assessed and parameters which might predict AF detection (clinical and from magnetic resonance tomography) were analysed. ILR implantation was performed in 123 patients on average 20 days after stroke. During a mean follow-up of 12.7±5.5 months, AF was documented and manually confirmed in 29 of 123 patients (23.6 %). First AF detection occurred on average after 3.6±3.4 months of monitoring. Patients with AF were on average older, had a higher CHA2DS2-VASc score and more often cerebral microangiopathy. In conclusion, AF can be documented in approximately 25 % of patients with the diagnosis of ESUS after careful work-up within a year of monitoring by an ILR and daily remote interrogation. This had important therapeutic consequences (initiation of anticoagulation for secondary stroke prevention) in these patients....
      PubDate: 2017-09-01 11:58:55
  • Ahead of print: Accumulating data on rivaroxaban for venous
           thromboembolism in clinical practice
    • Authors: S. Schulman (1)
      PubDate: 2017-08-31 14:12:24
  • Ahead of print: Apixaban and dalteparin in active malignancy associated
           venous thromboembolism
    • Authors: R. D. McBane (1); C. L. Loprinzi (1), A. Ashrani (1), J. Perez-Botero (1), R. A. Leon Ferre (1), S. Henkin (1), C. J. Lenz (1), J. G. Le-Rademacher (1), W. E. Wysokinski (1)
      Abstract: Currently, low molecular weight heparin (LMWH) is the guideline endorsed treatment of patients with cancer associated venous thromboembolism (VTE). While apixaban is approved for the treatment of acute VTE, there are limited data supporting its use in cancer patients. The rationale and design of this investigator initiated Phase IV, multicenter, randomized, open label, superiority trial assessing the safety of apixaban versus dalteparin for cancer associated VTE is provided (ADAM-VTE; NCT02585713). The main aim of the ADAM-VTE trial is to test the hypothesis that apixaban is associated with a significantly lower rate of major bleeding compared to dalteparin in the treatment of cancer patients with acute VTE. The primary safety outcome is rate of major bleeding. Secondary efficacy objective is to assess the rates of recurrent VTE or arterial thromboembolism. Cancer patients with acute VTE (n=300) are randomized to receive apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily thereafter) or dalteparin (200 IU/Kg daily for 30 days followed by 150 IU/kg daily thereafter) for 6 months. Stratification factors used for randomization include cancer stage and cancer specific risk of venous thromboembolism using the Khorana score. Participating centers are chosen from the Academic and Community Cancer Research United (ACCRU) consortium comprised of 90 oncology practices in the United States and Canada. Based on the hypothesis to be tested, we anticipate that these trial results will provide evidence supporting apixaban as an effective treatment of cancer associated VTE at lower rates of major bleeding compared to LMWH....
      PubDate: 2017-08-24 14:33:52
  • Ahead of print: Derivation and validation of a novel bleeding risk score
           for elderly patients with...
    • Authors: E. Seiler (1); A. Limacher (2), M. Mean (1, 3), H.-J. Beer (4), J. Osterwalder (5), B. Frauchiger (6), M. Righini (7), M. Aschwanden (8), C. M. Matter (9, 10), M. Banyai (11), N. Kucher (12), D. Staub (8), B. L&auml;mmle (13, 14), N. Rodondi (1, 15), A. Squizzato, D. Aujesky (1)
      Abstract: Existing clinical scores do not perform well in predicting bleeding in elderly patients with acute venous thromboembolism (VTE). We sought to derive an easy-to-use clinical score to help physicians identify elderly patients with VTE who are at high-risk of bleeding during extended anticoagulation (>3 months). Our derivation sample included 743 patients aged ≥65 years with VTE who were enrolled in a prospective multicenter cohort study. All patients received extended anticoagulation with vitamin K antagonists. We derived our score using competing risk regression, with the time to a first major bleeding up to 36 months of extended anticoagulation as the outcome, and 17 candidate variables as predictors. We used bootstrapping methods for internal validation. Sixty-six (9 %) patients suffered major bleeding. The clinical score is based on seven clinical factors (previous bleeding, active cancer, low physical activity, anemia, thrombocytopenia, antiplatelet drugs/NSAIDs, and poor INR control). Overall, 48 % of patients were classified as low-risk, 37 % as moderate-risk, and 15 % as high-risk of bleeding. The rate of major bleeding was 1.4 events in low-risk, 5.0 events in moderate-risk, and 12.2 events per 100 patient-years in high-risk patients. The c-statistic was 0.78 at 3 months and 0.71 at 36 months of extended anticoagulation. Model calibration was excellent (p=0.93). Internal validation showed similar results. This simple clinical score accurately identified elderly patients with VTE who are at high risk of major bleeding and who may not benefit from extended anticoagulation. Further validation of the score is important before its implementation into practice. The study is registered to as NCT00973596....
      PubDate: 2017-08-24 14:30:59
  • Ahead of print: Antithrombotic potency of ticagrelor versus clopidogrel in
           type-2 diabetic patients...
    • Authors: M. U. Zafar (1); M. Zafar (2), U. Baber (1), D. A. Smith (1), S. Sartori (1), J. Contreras (1), J. Rey-Mendoza (1), C. A. Linares-Koloffon (1), G. Escolar (1), R. Mehran (1), V. Fuster (1), J. J. Badimon (1)
      Abstract: Type-2 Diabetes Mellitus [T2DM] is associated with increased platelet reactivity and hypo-response to antiplatelet drugs. Ticagrelor, with its faster and more potent antiplatelet effects, was shown to reduce adverse events more than clopidogrel in the overall CAD patient population of PLATO trial, but the benefits did not reach statistical significance in the T2DM subgroup. To better understand these findings, we compared the antithrombotic effects of ticagrelor versus with clopidogrel in T2DM patients with cardiovascular disease. In a randomized, 2 treatment-sequence, crossover-design, T2DM patients (n=20, 57±8 years, 60 % male) received a loading-dose [LD] plus one week of daily-therapy [DT] of clopidogrel or ticagrelor. Treatment effects were assessed by measuring thrombus formation (Badimon Chamber) and platelet aggregation (Multiple Electrode Aggregometry (MEA) Analyzer and VerifyNow®) at 2- and 6-hour post-LD and on Day-7 of DT, in comparison with pre-treatment baseline. After 2 weeks of washout, patients switched to the second treatment under identical testing conditions. Ticagrelor significantly reduced thrombus formation versus baseline at 2- and 6-hour post-LD and Day-7 of DT (33 %, 40 % and 31 %, respectively, p<0.01 for all) whereas thrombus reductions with clopidogrel were much lower and significant only at 6-hour post-LD (16 %, 20 % and 17 %, respectively). Antithrombotic effect of ticagrelor at 6-hour was significantly stronger than clopidogrel (p<0.05). Platelet aggregation (MEA and VerifyNow®) was inhibited by both treatments but effects of ticagrelor were significantly stronger at each time-point. Ticagrelor exhibits a faster and more potent antithrombotic effect than clopidogrel in T2DM patients with cardiovascular disease, supporting its use in this population....
      PubDate: 2017-08-24 14:30:51
  • Ahead of print: Platelet count recovery and seroreversion in immune HIT
           despite continuation of...
    • Authors: A. W. Shih (1; 2), J.-A. I. Sheppard (3), T. E. Warkentin (4, 3, 2)
      Abstract: One of the standard distinctions between type 1 (non-immune) and type 2 (immune-mediated) heparin-induced thrombocytopenia (HIT) is the transience of thrombocytopenia: type 1 HIT is viewed as early-onset and transient thrombocytopenia, with platelet count recovery despite continuing heparin administration. In contrast, type 2 HIT is viewed as later-onset (i. e., 5 days or later) thrombocytopenia in which it is generally believed that platelet count recovery will not occur unless heparin is discontinued. However, older reports of type 2 HIT sometimes did include the unexpected observation that platelet counts could recover despite continued heparin administration, although without information provided regarding changes in HIT antibody levels in association with platelet count recovery. In recent years, some reports of type 2 HIT have confirmed the observation that platelet count recovery can occur despite continuing heparin administration, with serological evidence of waning levels of HIT antibodies ("seroreversion"). We now report two additional patient cases of type 2 HIT with platelet count recovery despite ongoing therapeutic-dose (1 case) or prophylactic-dose (1 case) heparin administration, in which we demonstrate concomitant waning of HIT antibody levels. We further review the literature describing this phenomenon of HIT antibody seroreversion and platelet count recovery despite continuing heparin administration. Our observations add to the concept that HIT represents a remarkably transient immune response, including sometimes even when heparin is continued....
      PubDate: 2017-08-24 14:30:43
  • Ahead of print: Clinical impact of major bleeding in patients with venous
           thromboembolism treated...
    • Authors: S. M. Bleker (1); &nbsp; M. P. A. Brekelmans (1), E. S. Eerenberg (1), A. T. Cohen (3), S. Middeldorp (1), G. Raskob (4), H. R. B&uuml;ller (1)
      Abstract: Factor Xa (fXa)-inhibitors are as effective and safer than vitamin-K–antagonists (VKA) in the treatment of venous thromboembolism (VTE). We previously classified the severity of clinical presentation and course of all major bleeding events from the EINSTEIN, AMPLIFY and HOKUSAI-VTE trials separately. The current aim was to combine these findings in order to increase precision, assess a class effect and analyse presentation and course for different types of bleeding, i. e. intracranial, gastro-intestinal, and other. We classified the clinical presentation and course of all major bleeding events using pre-defined criteria. Both classifications comprised four categories; one being the mildest, and four the most severe. Odds ratios (OR) were calculated for all events classified as category three or four between fXa-inhibitors and VKA recipients. Also, ORs were computed for different types of bleeding. Major bleeding occurred in 111 fXa-inhibitor recipients and in 187 LMWH/VKA recipients. The clinical presentation was classified as category three or four in 35 % and 48 % of the major bleeds in fXa inhibitor and VKA recipients, respectively (OR 0.59, 95 % CI 0.36–0.97). For intracranial, gastro-intestinal and other bleeding a trend towards a less severe presentation was observed for patients treated with fXa inhibitors. Clinical course was classified as severe in 22 % of the fXa inhibitor and 25 % of the VKA associated bleeds (OR 0.83, 95 % CI 0.47–1.46). In conclusion, FXa inhibitor associated major bleeding events had a significantly less severe presentation and a similar course compared to VKA. This finding was consistent for different types of bleeding....
      PubDate: 2017-08-17 14:10:59
  • Ahead of print: Hypofibrinogenaemia associated with novel Aα126Val→Asp
           mutation in the fibrinogen...
    • Authors: S. O. Brennan (1; 2), S. Brennan (3), A. D. Laurie (2)
      PubDate: 2017-08-17 14:06:13
  • Ahead of print: Coagulation factor XII regulates inflammatory responses in
           human lungs
    • Authors: R. Hess (1); L. Wujak (1), C. Hesse (2), K. Sewald (2), D. Jonigk (3), G. Warnecke (3), H. Fieguth (4), S. de Maat (5), C. Maas (5), F. Bonella (6), K. T. Preissner (1), B. Weiss (7), L. Schaefer (8), W. M. Kuebler (9, 10), P. Markart (11), M. Wygrecka (1)
      Abstract: Increased procoagulant activity in the alveolar compartment and uncontrolled inflammation are hallmarks of the acute respiratory distress syndrome (ARDS). Here, we investigated whether the contact phase system of coagulation is activated and may regulate inflammatory responses in human lungs. Components of the contact phase system were characterized in bronchoalveolar lavage fluids (BALF) from 54 ARDS patients and 43 controls, and their impact on cytokine/chemokine expression in human precision cut lung slices (PCLS) was assessed by a PCR array. Activation of the contact system, associated with high levels of coagulation factor XIIa (Hageman factor, FXIIa), plasma kallikrein and bradykinin, occurred rapidly in ARDS lungs after the onset of the disease and virtually normalized within one week from time of diagnosis. FXII levels in BALF were higher in ARDS non-survivors than survivors and were positively correlated with tumor necrosis factor (TNF)-α concentration. FXII induced the production and release of interleukin (IL)-8, IL-1β, IL-6, leukemia inhibitory factor (LIF), CXCL5 and TNF-α in human PCLS in a kallikrein-kinin-independent manner. In conclusion, accumulation of FXII in ARDS lungs may contribute to the release of pro-inflammatory mediators and is associated with clinical outcome. FXII inhibition may thus offer a novel and promising therapeutic approach to antagonize overwhelming inflammatory responses in ARDS lungs without interfering with vital haemostasis....
      PubDate: 2017-08-17 13:58:51
  • Ahead of print: Paracelsus, poison, and colistin
    • Authors: H. Herwald (1)
      PubDate: 2017-08-11 11:41:44
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