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1.
ESMO Open ; 5(3)2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32424065

RESUMO

INTRODUCTION: The role of the adaptive immune system in the pathophysiology of cancer-associated venous thromboembolism (VTE) has not been investigated in detail. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule responsible for immune evasion in several cancer entities, as expression on tumour cells silences the T cell-mediated immune response. Given the interrelation between inflammation, haemostasis and cancer, we aimed to investigate the association of players of the adaptive immunity (eg, lymphocytes, tumour PD-L1) with risk of VTE in patients with glioma, one of the most prothrombotic cancer types. METHODS: In this prospective observational single-centre cohort study, patients with newly diagnosed glioma or regrowth after resection were included. Primary endpoint was objectively confirmed VTE. At study inclusion, a blood draw was performed. Tumour PD-L1 expression was assessed via immunohistochemistry. RESULTS: In total, 193 patients were included. PD-L1 expression in ≥1% of tumour cells was observed in 20/193 (10.4%) glioma. In multivariable cox-regression analysis, on adjustment for age, sex and WHO grade IV, systemic lymphocyte counts were significantly associated with risk of VTE (HR per 1 G/L increase (95% CI): 1.15 (1.03 to 1.29), p=0.013). In contrast, no significant difference in risk of VTE was found regarding the PD-L1 status: the cumulative 24 months probability of VTE was 17.0% in patients with no PD-L1 and 11.8% in those with PD-L1 expressing tumours (p=0.663). CONCLUSION: In summary, PD-L1 expression was not associated with risk of VTE. Interestingly, peripheral lymphocytes, which are key players in adaptive immunity, were linked to an increased risk of glioma-associated VTE.

2.
Autoimmun Rev ; : 102525, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32240856

RESUMO

Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms. The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors. In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this field. TAKE HOME MESSAGES.

3.
Eur J Intern Med ; 2020 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-32317240

RESUMO

BACKGROUND: Bleeding assessment tools (BATs) have been developed to quantify bleeding severity. Their ability to predict for the diagnosis of a bleeding disorder has not been thoroughly investigated. OBJECTIVES: To evaluate the ability of the Vicenza BAT and the ISTH BAT to distinguish patients with an established bleeding disorder from those with bleeding of unknown cause (BUC). PATIENTS/METHODS: Three-hundred fifty-nine patients (228 with BUC, 64%) from the Vienna Bleeding Biobank were assessed in this study. RESULTS: The bleeding scores were similar in patients with an established diagnosis of a bleeding disorder compared to patients with BUC. Both BATs had a low sensitivity and specificity for the diagnosis of a bleeding disorder with areas under the receiver operating characteristic (ROC) curves of 0.53 (95% confidence interval 0.47-0.60) for the Vicenza BAT and 0.52 (0.46-0.59) for the ISTH BAT. In terms of specific diagnoses, both scores were most accurate in diagnosing von Willebrand disease (VWD, areas under the ROC curve; Vicenza BAT 0.67 (0.45-0.90); ISTH BAT 0.70 (0.50-0.90)). A separate evaluation of different bleeding symptoms in patients who had undergone surgery and tooth extraction revealed that postpartum bleeding and bleeding from small wounds was predictive for diagnosing a MBD in multivariable analysis. CONCLUSIONS: The Vicenza- and the ISTH BAT have a low ability to distinguish patients with an established bleeding disorder from those with BUC.

4.
Haemophilia ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227570

RESUMO

INTRODUCTION: The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half-life treatment for severe haemophilia A were demonstrated in the Phase 3 A-LONG and Kids A-LONG studies. Eligible subjects who completed A-LONG and Kids A-LONG could enrol in ASPIRE (NCT01454739), an open-label extension study. AIM: To report the long-term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. METHODS: Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. RESULTS: A total of 150 subjects from A-LONG and 61 subjects from Kids A-LONG enrolled in ASPIRE. Most subjects received the IP regimen (A-LONG: n = 110; Kids A-LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A-LONG and Kids A-LONG was 3.9 (0.1-5.3) years and 3.2 (0.3-3.9) years, respectively. No inhibitors were observed (0 per 1000 subject-years; 95% confidence interval, 0-5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was <1.0) and extended-dosing intervals were maintained (median of 3.5 days) for the majority of subjects in ASPIRE. CONCLUSION: ASPIRE results, which include up to 5 years of follow-up data, confirm earlier reports on the consistent and well-characterized safety and efficacy of rFVIIIFc treatment for severe haemophilia A.

5.
Atherosclerosis ; 298: 1-6, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32126388

RESUMO

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is common in patients with end-stage renal disease (ESRD) on hemodialysis (HD). However, antithrombotic therapy to prevent CVD increases the risk of bleeding. We aimed to investigate the prevalence of CVD and the practice patterns of antithrombotic agents in patients with ESRD on HD. METHODS: In a cross-sectional population based cohort of chronic HD patients (n = 626) from Vienna, Austria, the medical histories of patients and use of antithrombotic treatment were recorded, and the distribution of antithrombotic therapies for primary (n = 260, 41.5%) or secondary (n = 366, 58.5%) prevention of CVD was analyzed. RESULTS: Single antiplatelet therapy (SAPT) was used in 234 patients (37.4%), dual antiplatelet (DAPT) in 50 (8.0%), combination of anticoagulation and antiplatelet in 59 (9.4%), anticoagulation monotherapy in 78 (12.5%), and no antithrombotics in 205 patients (32.7%). The prevalence of CVD was 58.5%. In primary CVD prevention, 23.5% (n = 61) of patients were treated with SAPT. For secondary prevention, SAPT was used in 173 (47.3%), DAPT in 49 (13.4%), and dual antithrombotic therapies in 50 patients (13.7%), while 55 (15.0%) patients received no antithrombotics. Age (odds ratio [OR] per 1 year increase 0.96, 95%CI 0.94-0.99, p = 0.004) and hereditary nephropathy (OR 4.13, 95%CI 1.08-15.78, p = 0.038) were independently associated with the absence of antithrombotic therapy in secondary CVD prevention. CONCLUSION: The majority of patients did not receive antithrombotic therapy for primary prevention. Only 15% did not receive antithrombotic agents in the secondary prevention setting. The net-clinical benefit of antithrombotic therapy in ESRD needs to be determined.

6.
J Thromb Haemost ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32073229

RESUMO

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication of cancer. Elevated D-dimer is associated with an increased risk of cancer-associated VTE. Whether changes in D-dimer over time harbor additional prognostic information that may be exploited clinically for dynamic prediction of VTE is unclear. OBJECTIVES: To explore the potential role of longitudinal D-dimer trajectories for personalized prediction of cancer-associated VTE. PATIENTS/METHODS: A total of 167 patients with active malignancy were prospectively enrolled (gastrointestinal: n = 59 [35%], lung: n = 56 [34%], brain: n = 50 [30%], others: n = 2 [1%]; metastatic disease: n = 74 [44%]). D-dimer (median = 0.8 µg/mL [25th-75th percentile: 0.4-2.0]) was measured at baseline and during 602 monthly follow-up visits. Joint models of longitudinal and time-to-event data were implemented to quantify the association between D-dimer trajectories and prospective risk of VTE. RESULTS: VTE occurred in 20 patients (250-day VTE risk = 12.1%, 95% confidence interval [CI], 7.8-18.5). D-dimer increased by 34%/month (0.47 µg/mL/month, 95% CI, 0.22-0.72, P < .0001) in patients who developed VTE, but remained constant in patients who did not develop VTE (change/month = -0.06 µg/mL, 95% CI, -0.15 to 0.02, P = .121). In joint modeling, a doubling of the D-dimer trajectory was associated with a 2.8-fold increase in the risk of VTE (hazard ratio = 2.78, 95% CI, 1.69-4.58, P < .0001). This finding was independent of established VTE risk factors. Highly personalized, dynamic predictions of VTE conditional on individual patients' D-dimer trajectories could be obtained. CONCLUSIONS: D-dimer increases before the onset of cancer-associated VTE, but remains constant over time in patients without VTE. This study represents proof-of-concept that longitudinal trajectories of D-Dimer may advance the personalized assessment of VTE risk in the oncologic setting.

7.
J Thromb Haemost ; 18(5): 1081-1086, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32073230

RESUMO

BACKGROUND: Data on the effect of ABO blood group (ABO), von Willebrand factor (VWF) levels, and age on factor VIII (FVIII) in non-severe haemophilia A (HA) is scarce. OBJECTIVE: To investigate if ABO, VWF levels, and age have an influence on the variability of FVIII levels and consequently on the assessment of severity in non-severe HA. PATIENTS/METHODS: Eighty-nine patients with non-severe HA and 82 healthy controls were included. Data on ABO was collected and FVIII clotting activity (FVIII:C) with one-stage clotting assay (FVIII:C OSA) and chromogenic substrate assay (FVIII:C CSA), FVIII antigen (FVIII:Ag) and VWF antigen (VWF:Ag) and activity (VWF:Act) were determined. RESULTS: In HA, FVIII:C OSA and CSA and FVIII:Ag were not different between non-O (n = 42, median 15.5, interquartile range 10.4-24.0; 10.0, 6.8-26.0 and 15.2, 10.7-24.9) and O (n = 47, 14.1, 9.0-23.0; 10.0, 5.0-23.0 and 15.2, 9.3-35.5), whereas in healthy controls, non-O individuals had significantly higher FVIII levels. FVIII: C showed no relevant correlation with VWF levels in HA, but we observed strong correlations in healthy controls. Age had only a minor influence in HA, but had a considerable impact on FVIII:C in healthy controls. In multivariable regression analysis ABO, VWF:Ag and age were not associated with FVIII:C in HA, whereas this model explained 61.3% of the FVIII:C variance in healthy controls. CONCLUSIONS: We conclude that in non-severe HA ABO and VWF levels do not substantially influence the variability of FVIII levels and age has only minor effects on it, which is important information for diagnostic procedures.

8.
Thromb Res ; 187: 9-17, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31945589

RESUMO

BACKGROUND: Haemostatic activation and hypercoagulability are frequently observed in patients with metastatic colorectal cancer (mCRC), increase risk of venous thromboembolism (VTE) and have been implicated in tumour proliferation and progression. To date, the association of haemostatic biomarkers with oncologic outcomes including overall survival (OS), progression free survival (PFS) and disease control rate (DCR) is incompletely understood. METHODS: Within the framework of the Vienna Cancer and Thrombosis Study, a prospective observational cohort study, we conducted an exploratory analysis to investigate the association of six known biomarkers of haemostasis with oncologic outcomes in 99 patients with mCRC prior to chemotherapy initiation. RESULTS: Patients with high levels of factor VIII activity (FVIII), D-dimer, prothrombin fragment 1 + 2 (F1 + 2) and fibrinogen (defined as levels >75th percentile) had significantly shorter median OS than patients with lower levels. Elevation of four biomarkers was associated with mortality in multivariable analysis, adjusting for age, sex, number of metastatic sites and VTE (hazard ratio [95% CI] for death per doubling of levels: FVIII: 2.06 [1.28-3.30]; sP-selectin: 1.55 [1.07-2.24]; D-dimer: 1.40 [1.18-1.65]; F1 + 2: 1.64 [1.10-2.46]). Patients with elevated levels had numerically shorter median PFS across all markers and disease control rate (DCR) was significantly smaller in those with high levels of FVIII and F1 + 2 (adjusted odds ratio [95% CI] for DCR per doubling of levels: 0.23 [0.09-0.62] and 0.36 [0.16-0.82]) compared to patients with lower levels. CONCLUSION: Specific elevated haemostatic biomarkers are associated with higher mortality and partially with worse response to chemotherapy in patients with mCRC.

9.
Exp Mol Med ; 52(1): 66-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31956273

RESUMO

Patients with antiphospholipid syndrome (APS) are at high risk of developing venous and arterial thromboembolism (TE). The role of platelets in the pathogenesis of these prothrombotic conditions is not yet fully understood. The aim of this study was to gain mechanistic insights into the role of platelets in APS by comparing the platelet proteome between lupus anticoagulant (LA)-positive patients with (LA+ TE+) and without a history of TE (LA+ TE-) and healthy controls. The platelet proteome of 47 patients with LA, 31 with a history of TE and 16 without thrombotic history, and 47 healthy controls was analyzed by two-dimensional differential in-gel electrophoresis and mass spectrometry to identify disease-related proteins. Afterward, selected LA-related platelet proteins were validated by western blot and ELISA. Alterations of 25 proteins were observed between the study groups. STRING pathway analysis showed that LA-related protein profiles were involved in platelet activation, aggregation, and degranulation. For example, protein disulfide isomerase family members, enzymes that promote thrombosis, were upregulated in platelets and plasma of LA+ TE+ patients. Leukocyte elastase inhibitor (SERPINB1), an antagonist of neutrophil extracellular trap (NET) formation, was decreased in platelets of LA+ TE+ patients compared to healthy controls. Additionally, citrullinated histone H3, a NET-specific marker, was increased in plasma of LA+ TE+ patients. These findings suggest that decreased platelet SERPINB1 levels favor prothrombotic NETosis, especially in LA+ TE+ patients. Our findings reveal protein abundance changes connected to altered platelet function in LA-positive patients, thus suggesting a pathogenic role of platelets in thrombotic complications in APS.

10.
Haematologica ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974204

RESUMO

Macrophages are versatile cells that can be polarized by the tissue environment to fulfill required needs. Proinflammatory polarization is associated with increased tissue degradation and propagation of inflammation whereas alternative polarization within a Th2 cytokine environment is associated with wound healing and angiogenesis. To understand if polarization of macrophages can lead to a procoagulant macrophage subset we polarized human monocyte derived macrophages to a proinflammatory and an alternative activation state. Alternative polarization with interleukin-4 and IL-13 led to a macrophage phenotype characterized by increased tissue factor (TF) production and release and by an increase in extracellular vesicle production. In addition, also TF activity was enhanced in extracellular vesicles of alternatively polarized macrophages. This TF induction was dependent on signal transducer and activator of transcription-6 signaling and poly ADP ribose polymerase activity. In contrast to monocytes, human macrophages did not show increased tissue factor expression upon stimulation with lipopolysaccharide and interferon-γ. Previous polarization to either a proinflammatory or an alternative activation subset does not change the subsequent stimulation of TF. The inability of proinflammatory activated macrophages to respond to lipopolysaccharide and interferon-γ with an increase in TF production seems to be due to an increase in TF promoter methylation and was reversible when treating these macrophages with a demethylation agent. In conclusion, we provide evidence that proinflammatory polarization of macrophages does not lead to enhanced procoagulatory function, whereas alternative polarization of macrophages leads to an increased expression of TF and increased production of TF bearing extracellular vesicles by these cells suggesting a procoagulatory phenotype of alternatively polarized macrophages.

11.
ESMO Open ; 5(1)2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31958288

RESUMO

Patients with cancer are at an increased risk of symptomatic venous thromboembolism (VTE). In addition, an increasing number of patients with incidental thromboembolic events have been recorded in clinical practice. Therapeutic anticoagulation is crucial to prevent thrombus progression and reduce risk of recurrence; however, this comes at the price of an increased bleeding risk, which necessitates a personalised approach to choose the most appropriate type of therapy. Over the last decade, low-molecular-weight heparin has been the preferred anticoagulant agent for patients with cancer-associated thrombosis due to better efficacy and similar safety profile compared with vitamin K antagonists. While direct oral anticoagulants (DOAC) have emerged as new option for treatment of VTE in a general population, only limited data have been available specifically for patients with cancer until recently. Randomised, controlled trials have now been published, establishing DOAC as an alternative for the treatment of cancer-associated thrombosis. However, the improvement in the therapeutic armamentarium is accompanied by a number of special considerations. For instance, risk of bleeding is elevated in patients with cancer-associated VTE receiving DOAC, especially in certain tumour types (eg, gastrointestinal), and no guidance exists regarding their use in patients with severe thrombocytopaenia. Furthermore, DOAC are prone to certain drug-drug interactions and their effect might be altered due to nausea and vomiting in patients receiving chemotherapy. Here, we provide guidance on how to treat cancer-associated VTE and how new evidence from randomised controlled trials can be implemented in clinical practice. There are still clinical scenarios where robust evidence is lacking and treatment recommendations are based on extrapolations from other populations or expert opinion only. Therefore, additional research in special subpopulations is needed to optimise management of patients in challenging clinical scenarios.

12.
Transl Res ; 215: 41-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525325

RESUMO

A prothrombotic state is frequently observed in patients with cancer and contributes to the risks of venous thromboembolism (VTE), arterial thromboembolism (ATE), tumor progression, and death. Altered ex vivo properties of plasma clot formation and lysis have been observed in patients with cancer. The aim of this prospective study was to comprehensively characterize the relationship between plasma clot properties, inflammation, hypercoagulability, thrombotic complications, and mortality in patients with cancer using a tissue-factor-based turbidimetric assay of clot formation and lysis. Turbidity parameters were determined in 815 patients with newly-diagnosed or recurrent cancer and 97 healthy controls. Patients were followed-up for 2 years and rates of VTE (n = 72 events), ATE (n = 21 events), and death (n = 304 events) were assessed. Compared to controls, cancer patients' turbidity profiles showed an increased clot formation potential and higher resistance toward fibrinolysis. Elevated biomarkers of inflammation and hemostasis, such as C-reactive protein, FVIII, and thrombin generation explained substantial amounts of variation in turbidity parameters. In a prospective analysis, altered parameters of clot formation identified cancer patients at high risk of ATE (Hazard ratio [HR] per doubling of peak absorbance: 4.43, 95% CI: 1.50-13.07, P = 0.007) and death (HR per doubling of peak absorbance: 2.73, 2.00-3.72, P< 0.0001); these findings were independent of other prognostic covariates. Contrarily, turbidity parameters were not associated with risk of VTE (HR per doubling of peak absorbance: 1.15, 0.66-2.01, P = 0.62). We conclude that patients with cancer have altered ex vivo properties of clot formation which predict risks of ATE and mortality but not VTE.

13.
Thromb Haemost ; 120(2): 277-288, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31887776

RESUMO

BACKGROUND: Factor VIII (FVIII) products are usually dosed according to body weight (BW). This may lead to under- or over-dosing in underweight or obese patients, respectively. OBJECTIVE: This article evaluates the pharmacokinetics (PK) of recombinant FVIII concentrate, particularly recovery, in relation to body mass index (BMI) and other body composition descriptors. MATERIALS AND METHODS: Thirty-five previously treated adults with severe haemophilia A from five BMI categories (underweight, normal, overweight, obese class I and II/III) were included. PK was evaluated after 50 IU per kilogram of BW single-dose recombinant FVIII (turoctocog alfa). The body composition variable was based on measurements of weight, height, bioimpedance analysis, and dual-energy X-ray absorptiometry. A dosing model was derived to achieve similar peak FVIII activity levels across BMI categories. RESULTS: A statistically significant positive association between BMI and C30min, IR30min, and AUC0-inf was observed; CL and Vss showed a significant negative association with BMI; t½ was independent of BMI and other parameters. The dosing model introduced a correction factor 'M' for each BMI category, based on linear regression analysis of C30min against BMI, which ranged from 0.55 for underweight to 0.39 for obese class II/III. This model achieved similar peak FVIII activity levels across BMI categories, estimating an average dose adjustment of +243.3 IU (underweight) to -1,489.6 IU (obese class II/III) to achieve similar C30min. CONCLUSION: BMI appears to be the best predictor of recombinant FVIII recovery; however, PK endpoints were also dependent on other body composition variables. The model demonstrated that dosing can be adjusted for individual BMI to achieve better FVIII predictability across BMI categories.

14.
Blood ; 134(26): 2346-2353, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31697819

RESUMO

Genetic predispositions to venous thromboembolism (VTE) are relatively frequent in the general population and comprise a heterogeneous group of disorders. Whereas the most frequent congenital risk factors for thrombosis only moderately increase the risk, a deficiency in antithrombin (AT), one of the most important natural inhibitors of blood coagulation, carries a higher risk. Congenital AT deficiency is an infrequently encountered genetic risk factor for VTE, and different subtypes vary with regard to their thrombotic risk. Patients with congenital AT deficiency, especially those with quantitative deficiency (type 1), may develop thrombosis early in life and often have a conspicuous family history of first- and second-degree relatives with VTE. Women are particularly affected because of the risk potentiation by combined estrogen/progestogen oral contraceptive use or pregnancy. The lack of controlled trials or even observational studies of large cohorts does not allow therapeutic decisions to be based on scientific evidence. In this review, we will discuss cases with thrombotic manifestations and the tailored management of patients with this congenital thrombosis risk factor.

15.
Res Pract Thromb Haemost ; 3(4): 626-638, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31624782

RESUMO

Background: Specialty societies, such as the International Society on Thrombosis and Haemostasis (ISTH), are a key source of support for clinical and scientific communities, through the provision of educational activities, tools, and resources to support evidence-based care and high-quality, relevant basic science and clinical research. Objective: The aim of this study was to identify areas where the thrombosis and hemostasis (T&H) community is facing challenges and could benefit from the support of ISTH. Methods: A 3-phase, mixed-methods study consisting of semistructured individual interviews (phase 1), an online survey (phase 2), and discussion groups (phase 3) was conducted on the challenges experienced by the T&H community. Participants included physicians, clinical and basic science researchers, residents, fellows, students, and industry representatives. Qualitative data were analyzed using thematic analysis. Quantitative data were analyzed using frequency tables and chi-squares. Results: The study included 468 participants in interviews (n = 45), surveys (n = 404), and discussion groups (n = 19). Nine themes emerged that describe areas where the T&H community may benefit from additional support. Three areas were related to diagnosis and testing: thrombosis risk assessment, genetic testing, and diagnosis of von Willebrand disease (VWD). Another 3 were related to treatment decision making: use of anticoagulants with certain patients, preventive treatments in bleeding disorders, and VWD treatment. The remaining 3 were related to research: collaboration with/among researchers, collaboration between teams to collect data from human subjects, and promotion of basic science research. Conclusions: This study provides a comprehensive picture of priorities within the T&H community, which should inform the ISTH in its future interventions, including educational offerings and networking opportunities.

16.
J Clin Med ; 8(10)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581493

RESUMO

The exact contribution of neutrophils to post-resuscitative brain damage is unknown. We aimed to investigate whether neutrophil extracellular trap (NET) formation in the early phase after return of spontaneous circulation (ROSC) may be associated with poor 30 day neurologic function in cardiac arrest survivors. This study prospectively included adult (≥18 years) out-of-hospital cardiac arrest (OHCA) survivors with cardiac origin, who were subjected to targeted temperature management. Plasma levels of specific (citrullinated histone H3, H3Cit) and putative (cell-free DNA (cfDNA) and nucleosomes) biomarkers of NET formation were assessed at 0 and 12 h after admission. The primary outcome was neurologic function on day 30 after admission, which was assessed using the five-point cerebral performance category (CPC) score, classifying patients into good (CPC 1-2) or poor (CPC 3-5) neurologic function. The main variable of interest was the effect of H3Cit level quintiles at 12 h on 30 day neurologic function, assessed by logistic regression. The first quintile was used as a baseline reference. Results are given as crude odds ratio (OR) with 95% confidence interval (95% CI). Sixty-two patients (79% male, median age: 57 years) were enrolled. The odds of poor neurologic function increased linearly, with 0 h levels of cfNDA (crude OR 1.8, 95% CI: 1.2-2.7, p = 0.007) and nucleosomes (crude OR 1.7, 95% CI: 1.0-2.2, p = 0.049), as well as with 12 h levels of cfDNA (crude OR 1.6, 95% CI: 1.1-2.4, p = 0.024), nucleosomes (crude OR 1.7, 95% CI: 1.1-2.5, p = 0.020), and H3Cit (crude OR 1.6, 95% CI: 1.1-2.3, p = 0.029). Patients in the fourth (7.9, 95% CI: 1.1-56, p = 0.039) and fifth (9.0, 95% CI: 1.3-63, p = 0.027) H3Cit quintile had significantly higher odds of poor 30 day neurologic function compared to patients in the first quintile. Increased plasma levels of H3Cit, 12 h after admission, are associated with poor 30 day neurologic function in adult OHCA survivors, which may suggest a contribution of NET formation to post-resuscitative brain damage and therefore provide a therapeutic target in the future.

17.
Haemophilia ; 25(6): 1011-1019, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31621991

RESUMO

INTRODUCTION: BAY 94-9027 is an extended-half-life, site-specifically PEGylated, B-domain-deleted recombinant factor VIII (FVIII). The PROTECT VIII main study demonstrated efficacy of bleed control using extended-interval prophylaxis with BAY 94-9027 for 36 weeks. AIM: To report long-term efficacy and safety of prophylaxis with BAY 94-9027 in a descriptive analysis of the ongoing PROTECT VIII extension with a total treatment time of up to >5 years. METHODS: Previously treated males aged 12-65 years with severe haemophilia A who completed the PROTECT VIII main study were eligible for the open-label extension. Patients received on-demand treatment or prophylaxis (30-40 IU/kg twice weekly, 45-60 IU/kg every 5 days, or 60 IU/kg every 7 days) and could switch regimens as needed. RESULTS: Patients (N = 121; on demand, n = 14; prophylaxis, n = 107) accumulated a median (range) of 3.9 years (297-1965 days) and 223 (23-563) total exposure days by 31 January 2018. During the extension, median (quartile [Q]1; Q3) annualized bleeding rates (ABRs) for total bleeds were 1.6 (0.3; 4.6) for patients receiving prophylaxis and 34.1 (20.3; 36.6) for patients receiving on-demand treatment. ABRs for twice-weekly (n = 23), every-5-days (n = 33), every-7-days (n = 23) and variable frequency (n = 28) treatments were 1.7, 1.2, 0.7 and 3.1, respectively. Of prophylaxis patients, 20.6% were bleed-free throughout the extension (median time, 3.2 years), and 44.5% were bleed-free during the last 6 months. No patients developed FVIII inhibitors. CONCLUSIONS: BAY 94-9027 prophylaxis was efficacious and well tolerated with dosing intervals up to every 7 days for a median (range) of 3.9 years (0.8-5.4 years).

18.
Lancet Oncol ; 20(10): e566-e581, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31492632

RESUMO

Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer.

19.
Res Pract Thromb Haemost ; 3(3): 503-514, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31294335

RESUMO

Background: Cancer-associated venous thromboembolism (VTE) is an important complication in the course of a malignant disease. Low ADAMTS-13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13) and increased von Willebrand Factor (VWF) levels in cancer patients have been described numerously. Objectives: Investigation of the influence of ADAMTS-13 and VWF on the probability of VTE and survival in malignancy. Patients/Methods: In the framework of the ongoing prospective Cancer and Thrombosis Study (CATS) ADAMTS-13 activity and VWF antigen levels were investigated in cancer patients. Results: In total, 795 patients with various tumor types (364 female/431 male, median age 62 years) were included; of those, 56 developed VTE and 359 patients died during a median follow-up time of 730 days. The hazard ratio (HR) of VTE per doubling of VWF level was 1.56 (95% confidence interval [CI] 1.13-2.16) in multivariable competing risk analysis. ADAMTS-13 levels showed no correlation with the incidence of VTE in univariate competing risk analysis. The HR of mortality per doubling of VWF level was 1.46 (95% CI 1.28-1.66) and per SD increment of ADAMTS-13was 0.90 (95% CI 0.81-1.00) in multivariable Cox regression analysis. Patients with VWF >75th percentile and concomitant low (<25th percentile) or medium (25-75th percentile) ADAMTS-13 values had the highest probability of mortality (HR 4.31 and 4.75, respectively). Conclusions: High VWF levels were significantly associated with the risk of developing VTE in cancer patients, whereas ADAMTS-13 was not. Low ADAMTS-13 and increased VWF levels were independently associated with worse overall survival.

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