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Bleeding Tendency

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Claudio Gonzalez – One of the best experts on this subject based on the ideXlab platform.

  • Bleeding Tendency in dual antiplatelet therapy with aspirin clopidogrel rescue of the template Bleeding time in a single center prospective study
    Thrombosis Journal, 2012
    Co-Authors: Raul Altman, Claudio Gonzalez, Ana J Rivas

    Abstract:

    Background
    Patients with heightened platelet reactivity in response to antiplatelet agents are at an increased risk of recurrent ischemic events. However, there is a lack of diagnostic criteria for increased response to combined aspirin/clopidogrel therapy. The challenge is to identify patients at risk of Bleeding. This study sought to characterize Bleeding Tendency in patients treated with aspirin and clopidogrel.

  • Bleeding Tendency in dual antiplatelet therapy with aspirin/clopidogrel: rescue of the template Bleeding time in a single-center prospective study
    Thrombosis Journal, 2012
    Co-Authors: Raul Altman, Ana J Rivas, Claudio Gonzalez

    Abstract:

    Background
    Patients with heightened platelet reactivity in response to antiplatelet agents are at an increased risk of recurrent ischemic events. However, there is a lack of diagnostic criteria for increased response to combined aspirin/clopidogrel therapy. The challenge is to identify patients at risk of Bleeding. This study sought to characterize Bleeding Tendency in patients treated with aspirin and clopidogrel.

Edward G D Tuddenham – One of the best experts on this subject based on the ideXlab platform.

  • α1 antitrypsin pittsburgh in a family with Bleeding Tendency
    Haematologica, 2009
    Co-Authors: Yan Liang, Yongqiang Zhao, Edward G D Tuddenham

    Abstract:

    We describe a 16-year-old girl and her 41-year-old father who both had a Bleeding Tendency, dramatic prolongation of all standard clotting assays, undetectable levels of plasma protein C activity, and low or borderline levels of factors X, XI and XII. Plasma and serum electrophoresis revealed a minor peak following the main α1 globulin peak, of which the proportion was increased. Platelet aggregation by thrombin (final concentration 1 U/mL) was absent in both patients, but this inhibition can be overcome by increasing the concentration of thrombin (4 U/mL). The molecular defect responsible for these coagulation abnormalities was identified by genomic sequencing. Both patients are heterozygous for α1-antitrypsin Met 358 to Arg (α1-antitrypsin Pittsburgh). Seven other members of this pedigree had normal coagulation tests and do not carry the same genetic mutation. This unique family with α1-antitrypsin Pittsburgh sheds some light on the study of this extremely rare mutation and its inheritance.

  • definition of the Bleeding Tendency in factor xi deficient kindreds a clinical and laboratory study
    Thrombosis and Haemostasis, 1995
    Co-Authors: P H B Boltonmaggs, D A Patterson, R T Wensley, Edward G D Tuddenham

    Abstract:

    : Individuals with severe factor XI deficiency are prone to excessive Bleeding after injury or surgery, but the existence of a haemorrhagic Tendency in partial factor XI deficiency is controversial. In this study, 172 members of 30 kindreds (20 non-Jewish) transmitting factor XI deficiency in North West England were interviewed and a Bleeding history questionnaire completed. Blood was taken for coagulation assays. The questionnaires were categorised independently by two assessors to determine presence or absence of a Bleeding Tendency, in the absence of information about the factor XI level or family history. Analysis shows that 48% of heterozygotes have a Bleeding Tendency. Eighteen (60%) families came to attention because of Bleeding problems in heterozygotes. Comparison of histories between partially deficient and non-deficient individuals demonstrated a higher incidence of menstrual problems, an increase in significant bruising, and an increased likelihood of excessive Bleeding after tonsillectomy and dental extractions. The incidence of von Willebrand’s disease was not increased, but individuals with heterozygous factor XI deficiency who were bleeders tended to have lower levels of factor VIIIc and von Willebrand factor, and were more commonly of blood group 0. These features may contribute to the Bleeding Tendency. There was no evidence of alteration in factor VII activity (as defined by the ratio of activity to antigen) between the bleeders and non-bleeders. This is convincing evidence for abnormal Bleeding in factor XI deficiency which is not confined to severely deficient patients.

Ingrid Pabinger – One of the best experts on this subject based on the ideXlab platform.

  • ristocetin induced platelet aggregation for monitoring of Bleeding Tendency in ibrutinib treated patients with chronic lymphocytic leukemia
    Blood, 2015
    Co-Authors: Lukas Kazianka, Ingrid Pabinger, Christa Drucker, Cathrin Skrabs, Philipp B Staber, Edit Porpaczy, Christine Einberger, Marion Heinz, Alexander W Hauswirth, Peter Quehenberger

    Abstract:

    Background. Inhibition of Bruton´s tyrosine kinase (BTK) with the small molecule ibrutinib has significantly improved the survival of patients with chronic lymphocytic leukemia (CLL). BTK is also expressed in platelets. Collagen- and von Willebrand Factor (vWF)-dependent (ristocetin-induced) impairment of platelet function has recently been described (Levade M et al., Blood 2014, 124:3991-5;Kamel S et al., Leukemia 2015, 29:783-787) . Bleeding events were observed in 61% of patients in a recently published 3 year follow-up (Byrd JC et al., Blood 2015, 125:2497-2506). Bleeding under ibrutinib is generally mild (CTC grade 1-2 corresponding to spontaneous bruising or petechiae), but grade 3 or 4 Bleeding can be observed, particularly after trauma. We hypothesized that quantitative assessment of platelet aggregation in ibrutinib CLL patients could help (1) to predict Bleeding Tendency, and (2) to guide patients through invasive procedures. Patientsand Methods. Twenty-four adult patients with previously treated CLL (16 male/8 female, median age 67 years, range 55-84) received ibrutinib orally at a planned dose of 420mg/day and were regularly monitored and thoroughly investigated for Bleeding Tendency. The median time on ibrutinib was 7.5 months, (range 1-27). Bleeding events (any CTC grade) occurred in 13 (54%) and dose-reductions to 280 (N=12) or 140mg (N=3) (for Bleeding, infections, or neutropenia) were made in 15 (63%) of patients during a median observation period of 5 months (range 1-12). Bleeding was observed in 4 of 6 patients with concomitant anticoagulation. Of note, only 1 of the 24 patients had a CTC grade 3 Bleeding event, and no grade 4 or 5 events were observed. Ristocetin-induced platelet aggregation (RIPA, herein referred to as RCoF) was quantitatively measured in fresh hirudin-blood by whole blood aggregometry with a Multiplate® Analyzer (Roche Diagnostics). Platelet aggregation was expressed in AUC units (U) (normal range 98-180U). Controls included normal subjects (N=53). Consecutive samples before and during treatment were available in all patients. Statistical methods comprised t-Test and ANOVA using SAS. Results. Ristocetin-induced platelet aggregation was already diminished before ibrutinib treatment (median 51 RCoF U) when compared to normal controls (Table 1). This is likely due to lower platelet counts in CLL patients influencing overall platelet aggregability (Hanke AA et al., Eur J Med Res 2010, 15:214-219). During ibrutinib treatment, platelet aggregation was substantially impaired (median of 22U). A direct comparison of available paired samples in 5 patients showed a significant decrease after ibrutinib initiation (51 to 14.5U; p=0.0028). Of note, significantly lower values were measured at visits when Bleeding events were documented (N=34) compared to patient visits without Bleeding Tendency (N=70) (median 13 vs. 42U; p 2 (N=10) vs. Conclusion. These data indicate that quantitative assessment of vWF-dependent platelet function in ibrutinib treated patients may serve to monitor therapy particularly in the setting of Bleeding Tendency, anticoagulation, or planned invasive procedures. Further evaluation of platelet function as a pharmacodynamic marker seems warranted. Disclosures Staber:Genactis: Research Funding; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Takeda-Millenium: Research Funding; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Pabinger:Boehringer Ingelheim: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees; Bayer: Membership on an entity9s Board of Directors or advisory committees; GSK: Membership on an entity9s Board of Directors or advisory committees; CSL Behring: Membership on an entity9s Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Membership on an entity9s Board of Directors or advisory committees; Baxter: Membership on an entity9s Board of Directors or advisory committees. Jilma:True North Therapeutics, Inc.: Consultancy, Research Funding. Jaeger:Hoffmann La Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; True North Therapeutics, Inc.: Research Funding.

  • decreased adamts13 activity levels in patients with a Bleeding Tendency of unknown origin
    Blood, 2011
    Co-Authors: Johanna Haselboeck, Cihan Ay, Ingrid Pabinger, Moritz Lambers, Clarissa Laszkovics, Daniela Manner, Ulrike Nowakgoettl

    Abstract:

    Abstract 1218 Background: ADAMTS13 ( A D isintegrin-like A nd M etalloproteinase domain with T hrombo S pondin type 1 domains) is a 190 kDa glycosylated protein, which cleaves ultra-large vWF multimers, reduces platelet adhesion and aggregation and down regulates thrombus formation and inflammation. This metalloproteinase is synthesized in the liver and the vascular endothelium. Reduction or absence of ADAMTS13 activity is associated with impaired degradation of ultra-large vWF multimers and excessive vWF-induced platelet aggregation on the vascular endothelium, as seen in thrombotic thrombocytopenic purpura (TTP). An imbalance in the size of vWF multimers causes thrombosis in the microvasculature, but has also been reported to be associated with Bleeding. No physiological regulative mechanism of ADAMTS13 activity is known so far. Proteolysis of ADAMTS13 in vivo has just been reported in sepsis or a rare case of α2-antiplasmin deficiency, in which plasmin cleaves ADAMTS13, and ADAMTS13 levels in patients with a Bleeding Tendency has not been investigated so far: This study aimed to investigate ADAMTS13 levels in pediatric and adult patients with a Bleeding Tendency of unknown origin. Patients and Methods: 250 white patients [150 children & 100 adults] with a median (min-max) age of 14.0 (0.1–85.0) years [female: 56.4%] with a Bleeding Tendency of unknown origin and 232 age- and sex-matched healthy controls [130 children & 102 adults], were enrolled at the University of Munster (Germany) and the Department of Medicine I, Division of Hematology and Hemostaseology at the Medical University of Vienna. Patients with established Bleeding disorders, such as hemophilia A and B, von Willebrand syndrome, thrombocytopenia or severe platelet function disorders were not included. Further exclusion criteria were abnormal global clotting tests, severe anemia, acute infection/sepsis or liver disease. The investigation was performed according to the Declaration of Helsinki and all participants and/or their parents gave written informed consent before study inclusion. ADAMTS13 activity was determined by ELISA (Technozym®, Technoclone, Vienna, Austria) beyond the acute Bleeding episode. Non-parametric statistics were performed for descriptive analysis [median (min-max) values] and inter-group comparisons [Mann-Whitney U test]. Odds ratios [ORs] with corresponding 95% confidence intervals [CIs] were estimated by multivariate analysis using a logistic regression model, adjusted for age at blood sampling, FVIII, vWF antigen and blood group. For all analyses, a two-sided P -value Results: ADAMTS13 activity levels [%] were significantly lower in patients compared to controls (p th percentile was 36.4% [children 33.3%; adults 41%] in patients compared to 23.3% [children 22.3%; adults 24.5%] in the control group [p=0.001]. In multivariate analysis, the association of ADAMTS13 levels Conclusion: ADAMTS13 activity levels are significantly lower in patients with Bleeding of unknown origin compared to healthy controls. The results were consistent in pediatric and adult patients. A possible protective counter-regulation of ADAMTS13 levels to reduce vWF cleavage may be speculated. However, the underlying mechanisms still have to be elucidated. Disclosures: No relevant conflicts of interest to declare.

  • thrombin generation in patients with a Bleeding Tendency of unknown origin
    Annals of Hematology, 2011
    Co-Authors: Cihan Ay, Johanna Haselbock, Clarissa Laczkovics, Silvia Koder, Ingrid Pabinger

    Abstract:

    There are a number of persons with a mild to moderate Bleeding Tendency, in whom no underlying Bleeding disorder can be detected despite thorough investigation of all known heritable and acquired haemostatic abnormalities. Thrombin is the central enzyme in the coagulation cascade, which is important for sufficient haemostasis. The measurement of an individual’s potential to generate thrombin has been proposed for estimating the individual coagulation potential and predicting a hyper- or hypo-coagulable phenotype. The aim of our study was to investigate in vivo thrombin generation in a case-control study of patients with a Bleeding Tendency of unknown origin and in age- and sex-matched healthy individuals. Bleeding Tendency was classified according to a standardized Bleeding score. Thrombin generation was measured with a commercially available assay (Technothrombin-TGA, Technoclone, Vienna, Austria). In total, 101 patients (76 female; median age [25th–75th percentile], 44 [35–60] years) and 102 controls (67 women; median age, 47 [38–55] years) were enrolled. The distribution of parameters of thrombin generation among patients and controls showed no statistically significant difference: lag phase (14.4 [11.1–18.1] vs. 14.1 [12.1–17.1] min, p = 0.720), peak thrombin (179.8 [135.6–242.6] vs. 175.1 [143.1–261.4] nM, p = 0.576), time to peak thrombin (23.6 [18.1–28.6] vs. 22.6 [18.6–27.1] min, p = 0.790), velocity index (19.7 [13.0–39.0] vs. 22.6 [14.5–36.5] nM/min, p = 0.233) and area under the thrombin generation curve (3,491 [3,069–3,880] vs. 3,414 [3,045–3,750] nM thrombin, p = 0.673). In conclusion, the thrombin generation potential in patients with a Bleeding Tendency of unknown origin was not different from that of healthy individuals.