Thalidomide for the Management of Gastrointestinal Bleeding in a Palliative Care Setting.

BACKGROUND: Palliative care patients frequently present with clinically significant gastrointestinal bleeding. Due to the existence of confounding comorbidities and a remarkably reduced state of general health in many cases, the management of gastrointestinal bleeding in this population is often challenging. SUMMARY: This review summarizes and discusses the role of thalidomide in gastrointestinal bleeding with a special focus on palliative care patients. In addition, an illustrative case report is presented. Thalidomide may be beneficial in gastrointestinal bleeding by exerting antiangiogenic effects. The drug has an acceptable safety profile. Side effects like neurotoxicity may limit its use but can be monitored safely. Due to thalidomide's thrombin generation potential, patients managed with thalidomide-containing regimes should be closely monitored for deep venous thrombosis. Given its teratogenicity, thalidomide should not be administered to women of childbearing potential who are not using adequate contraception. KEY MESSAGE: Physicians caring for patients in a palliative care setting should be aware of thalidomide as an effective therapeutic option when endoscopy fails to find a bleeding source or for those patients who cannot or refuse to undergo endoscopy but present with recurrent or obscure gastrointestinal bleeding.

Pharmacokinetic-guided versus standard prophylaxis in hemophilia: a systematic review and meta-analysis.

BACKGROUND: With population pharmacokinetic (PK) modeling more readily available and PK-guided prophylaxis endorsed by current hemophilia guidelines, we conducted a systematic review to summarize current evidence in the literature. OBJECTIVES: To assess the efficacy of PK-guided compared with non-PK-guided prophylaxis. METHODS: We did not restrict inclusion to specific study design labels and included all studies consisting of at least one distinct cohort arm receiving PK-guided prophylaxis. We searched the following databases from inception to date of search: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the EU Clinical Trial Register. Following title, abstract, and full-text screening conducted independently by 2 review authors, we summarized studies qualitatively and synthesized included randomized clinical trials (RCTs) quantitatively by fitting random-effects models. RESULTS: Search of databases on February 3, 2023, yielded 25 studies fitting our inclusion criteria. Of those, only 2 RCTs and 17 nonrandomized studies included a standard prophylaxis comparator group. Furthermore, risk of bias in the latter was substantial, primarily due to before-after study designs and retrospective comparator groups. Thus, nonrandomized studies were only presented qualitatively. A random-effects meta-analysis of the 2 identified RCT remained inconclusive with regards to bleeding outcomes (ratio of means, 1.15; 95% CI, 0.85-1.56) and factor consumption (ratio of means, 0.82; 95% CI, 0.58-1.18). CONCLUSION: Evidence in the literature suggesting a clinical benefit of PK-guided over standard fixed-dose prophylaxis was weak and mainly found in nonrandomized studies limited by lack of concurrent controls, heterogeneity in outcome reporting, small sample sizes, and high risk of bias.

Atrial fibrillation and cancer: prevalence and relative risk from a nationwide study.

Background: Atrial fibrillation (AF) is an increasingly recognized codiagnosis in patients with cancer. Objectives: This study aimed to provide a robust and contemporary estimate on the coprevalence and relative risk of AF in patients with cancer. Methods: We conducted a nationwide analysis, utilizing diagnosis codes from the Austrian Association of Social Security Providers dataset. Estimates of the coprevalence of cancer and AF and the relative risk of AF in patients with cancer compared with individuals without cancer were obtained as point prevalences with binomial exact confidence intervals and summarized across age groups and cancer types with random-effects models. Results: Overall, 8,306,244 persons were included in the present analysis, of whom 158,675 (prevalence estimate, 1.91%; 95% CI, 1.90-1.92) had a cancer diagnosis code and 112,827 (1.36%; 95% CI, 1.35-1.36) an AF diagnosis code, respectively. The prevalence estimate for AF in patients with cancer was 9.77% (95% CI, 9.63-9.92) and 1.19% (95% CI, 1.19-1.20) in the noncancer population. Conversely, 13.74% (95% CI, 13.54-13.94) of patients with AF had a concurrent cancer diagnosis. The corresponding age-stratified random-effects relative risk ratio for AF in patients with cancer compared with no cancer diagnosis was 10.45 (95% CI, 7.47-14.62). The strongest associations between cancer and AF were observed in younger persons and patients with hematologic malignancies. Conclusion: Cancer and AF have a substantial coprevalence in the population. This finding corroborates the concept that cancer and AF have common risk factors and pathophysiology.

Bleeding phenotype in nonsevere hemophilia by International Society on Thrombosis and Haemostasis bleeding assessment tool, bleeding frequency, and the joint status.

Background: Although the phenotype of severe hemophilia has been well studied, there are still knowledge gaps in nonsevere hemophilia. Objectives: The objective of this study was to characterize the clinical bleeding phenotype in nonsevere hemophilia and its association with different factor VIII/IX assessments. Methods: This was a cross-sectional, multicenter study to investigate the bleeding phenotype in adults with nonsevere hemophilia by the number of bleeding and joint bleeding in the past 5 years, a joint score, and the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT). Factor levels were analyzed by 1-stage (lowest in history and at study inclusion) and chromogenic assay (at study inclusion). Patients were enrolled between March 2015 and May 2019. Results: Of the 111 patients (86 with mild and 25 with moderate hemophilia), 57 patients (54.8%) reported any bleeding and 24 (23.1%) any joint bleeding in the past 5 years. A joint score ≥1 was found in 44 patients (41.9%), an ISTH-BAT ≥4 in 100 patients (90.1%), and an ISTH-BAT joint item ≥1 in 50 patients (45.0%). Within the ISTH-BAT, muscle and joint bleeds showed the largest difference between mild and moderate hemophilia. The lowest factor VIII/IX level in patients' history was best associated with bleeding outcomes. Factor was inversely associated with joint bleeds (incidence rate ratio 0.88; 95% CI, 0.79-0.98), joint score, and ISTH-BAT (odds ratios from proportional odds ordinal logistic regression 0.92; 95% CI, 0.87-0.97; and 0.89; 95% CI, 0.86-0.93, respectively). Conclusion: The occurrence of joint bleeding differentiated persons with mild and moderate hemophilia. The ISTH-BAT and lowest factor in patients' history provided valuable information of the bleeding phenotype in nonsevere hemophilia.

Circulatory miR-411-5p as a Novel Prognostic Biomarker for Major Adverse Cardiovascular Events in Patients with Atrial Fibrillation.

The risk stratification of patients with atrial fibrillation (AF) for subsequent cardiovascular events could help in guiding prevention strategies. In this study, we aimed at investigating circulating microRNAs as prognostic biomarkers for major adverse cardiovascular events (MACE) in AF patients. We conducted a three-stage nested case-control study within the framework of a prospective registry, including 347 AF patients. First, total small RNA-sequencing was performed in 26 patients (13 cases with MACE) and the differential expression of microRNAs was analyzed. Seven candidate microRNAs with promising results in a subgroup analysis on cardiovascular death were selected and measured via using RT-qPCR in 97 patients (42 cases with cardiovascular death). To further validate our findings and investigate broader clinical applicability, we analyzed the same microRNAs in a subsequent nested case-control study of 102 patients (37 cases with early MACE) by using Cox regression. In the microRNA discovery cohort (n = 26), we detected 184 well-expressed microRNAs in circulation without overt differential expression between the cases and controls. A subgroup analysis on cardiovascular death revealed 26 microRNAs that were differentially expressed at a significance level < 0.05 (three of which with an FDR-adjusted p-value <0.05). We, therefore, proceeded with a nested case-control approach (n = 97) focusing on patients with cardiovascular death and selected, in total, seven microRNAs for further RT-qPCR analysis. One microRNA, miR-411-5p, was significantly associated with cardiovascular death (adjusted HR (95% CI): 1.95 (1.04-3.67)). Further validation (n = 102) in patients who developed early MACE showed similar results (adjusted HR (95% CI) 2.35 (1.17-4.73)). In conclusion, circulating miR-411-5p could be a valuable prognostic biomarker for MACE in AF patients.

Characterization of a prothrombotic phenotype using thrombin generation and thrombin activity in cirrhosis and portal hypertension.

BACKGROUND: Patients with advanced chronic liver disease (ACLD) may develop a prothrombotic phenotype that seems to be more pronounced with more severe liver dysfunction. An imbalance of endogenous pro- and anticoagulants is not fully captured by routine coagulation assays. METHODS: In a cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement, we assessed thrombin generation (TGA) using two commercially available assays (Technothrombin and Thrombinoscope) with and without addition of soluble thrombomodulin (TM), as well as thrombin activity, alongside a panel of coagulation parameters. RESULTS: The cohort encompassed 37 patients (median age 55.3 years, mean HVPG 16 ± 5 mm Hg). In the TM-modified Thrombinoscope TGA, the endogenous thrombin generation potential (ETP) was significantly increased in Child-Pugh-Score (CPS) B/C patients (N = 23, 62 %) compared to CPS A patients (N = 14, 38 %) (ETP: 546 nM∗min (443-696) vs. 404 nM∗min (289-573), p = 0.028). Using the Technothrombin TGA without TM, patients with CPS B/C had decreased ETP compared to CPS A patients (ETP: 2792 ± 1336 nM∗min vs. 5040 ± 816 nM∗min, p < 0.001) and with addition of TM (final concentration: 5 nM; ETP: 2545 ± 1327 nM∗min vs. 4824 ± 929 nM∗min, p < 0.001). Thrombin activity levels were 0.6pM in median (0.2-1.6pM) and above the level of detectability (0.10pM) in 94.6 % of patients but were not correlated to severity of cirrhosis (CPS A 0.7pM vs CPS B/C 0.4pM, p = 0.377) nor to parameters of TGA. CONCLUSION: Thrombin plasma levels are elevated in liver disease patients without apparent correlation to TGA or severity of cirrhosis. TGAs can be modified with TM to enable protein C-dependent anticoagulation, but result in differences with regard to severity of liver disease.

The post-VTE functional status scale for assessment of functional limitations in patients with venous thromboembolism: Construct validity and responsiveness in a prospective cohort study.

BACKGROUND: A large proportion of patients experience functional limitations after an acute episode of venous thromboembolism (VTE). Recently, the post-VTE functional status (PVFS) scale was proposed to capture these limitations. We performed a prospective cohort study to validate this scale. METHODS: The PVFS scale, PROMIS physical function 10a, EQ-5D-5L, and disease-specific quality of life (VEINES-QOL/Sym, PEmb-QoL) were assessed within three weeks of VTE diagnosis and after a median (IQR) follow-up of 13.4 (12.7-15.9) weeks. To evaluate construct validity of the PVFS scale, we determined correlations of PVFS scale with the other health measurements and investigated differences in patients above/below 70 years. Responsiveness was evaluated with a linear regression model, predicting change in PROMIS with change in PVFS scale. RESULTS: We included 211 patients (median (IQR) age: 55.1 (44.1-67.6) years, 40 % women). Pulmonary embolism was diagnosed in 105 (49.8 %) patients and 62.6 % of events were unprovoked. The PVFS scale correlated with PROMIS physical function (Spearman's rho (r): -0.67 and -0.63, p < 0.001) and EQ-5D-5L index (r = -0.61 and -0.61, p < 0.001) at baseline and follow-up. Furthermore, PVFS correlated moderately to strongly with disease-specific quality of life. Patients >70 years had significantly higher PVFS grades at follow-up (median (IQR): 2 (0-3) vs. 1 (0-2), p = 0.010). Changes in PVFS scale over time were significantly associated with changes in PROMIS physical function. CONCLUSIONS: The PVFS scale showed adequate construct validity and responsiveness in a prospective cohort study of patients with VTE, suggesting that it can be incorporated as additional health measurement and outcome parameter in research and clinical practice.

Growth differentiation factor-15 predicts major bleeding, major adverse cardiac events and mortality in patients with end-stage kidney disease on haemodialysis: findings from the VIVALDI study.

BACKGROUND: Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular events and bleeding. Optimizing risk assessment of ESKD patients regarding the risk of thromboembolism and bleeding complications in comorbid conditions, including atrial fibrillation and coronary heart disease, is challenging. To improve risk prediction we investigated growth differentiation factor-15 (GDF-15), a promising cardiovascular biomarker, and its relation to adverse outcomes. METHODS: In this prospective, multicentre, population-based cohort study, GDF-15 was measured in 594 ESKD patients on haemodialysis (median age 66 years, 38% female), who were followed up for a median of 3.5 years. The association of GDF-15 with major bleeding, arterial thromboembolism, major adverse cardiac events (MACE) and death was analysed within a competing risk framework. Further, we evaluated the additive predictive value of GDF-15 to cardiovascular and death risk assessment. RESULTS: GDF-15 levels were in median 5475 ng/l (25th-75th percentile 3964-7533) and independently associated with major bleeding {subdistribution hazard ratio [SHR] 1.31 per double increase [95% confidence interval (CI) 1.00-1.71]}, MACE [SHR 1.47 (95% CI 1.11-1.94)] and all-cause mortality [SHR 1.58 (95% CI 1.28-1.95)] but not arterial thromboembolism [SHR 0.91 (95% CI 0.61-1.36)]. The addition of GDF-15 to the HAS-BLED score significantly improved discrimination and calibration for predicting major bleeding [C-statistics increased from 0.61 (95% CI 0.52-0.70) to 0.68 (95% CI 0.61-0.78)]. Furthermore, we established an additive predictive value of GDF-15 beyond current risk models for predicting MACE and death. CONCLUSION: GDF-15 predicts the risk of major bleeding, cardiovascular events and death in ESKD patients on haemodialysis and might be a valuable marker to guide treatment decisions in this challenging patient population.

Antithrombin Activity and Association with Risk of Thrombosis and Mortality in Patients with Cancer.

Venous and arterial thromboembolism (VTE/ATE) are common complications in cancer patients. Antithrombin deficiency is a risk factor for thrombosis in the general population, but its connection to risk of cancer-associated thrombosis is unclear. We investigated the association of antithrombin activity levels with risk of cancer-associated VTE/ATE and all-cause mortality in an observational cohort study including patients with cancer, the Vienna Cancer and Thrombosis Study. In total, 1127 patients were included (45% female, median age: 62 years). Amongst these subjects, 110 (9.7%) patients were diagnosed with VTE, 32 (2.8%) with ATE, and 563 (49.9%) died. Antithrombin was not associated with a risk of VTE (subdistribution hazard ratio (SHR): 1.00 per 1% increase in antithrombin level; 95% CI: 0.99-1.01) or ATE (SHR: 1.00; 95% CI: 0.98-1.03). However, antithrombin showed a u-shaped association with the risk of all-cause death, i.e., patients with very low but also very high levels had poorer overall survival. In the subgroup of patients with brain tumors, higher antithrombin levels were associated with ATE risk (SHR: 1.02 per 1% increase; 95% CI: 1.00-1.04) and mortality (HR: 1.01 per 1% increase; 95% CI: 1.00-1.02). Both high and low antithrombin activity was associated with the risk of death. However, no association with cancer-associated VTE and ATE across all cancer types was found, with the exception of in brain tumors.

Atrial fibrillation and anticoagulation are associated with hospitalisations in patients with end-stage kidney disease on haemodialysis: a prospective population-based cohort study.

BACKGROUND: Patients with end-stage kidney disease on haemodialysis suffer from frequent complications requiring hospitalisation. Atrial fibrillation is a burdensome comorbidity amongst patients on haemodialysis. We aimed to assess frequency, reasons, and duration of hospitalisations in haemodialysis patients and their association with atrial fibrillation and anticoagulation. METHODS: Prevalent patients with end-stage kidney disease on haemodialysis were recruited into a prospective cohort study and observed for a median observation time of 3.4 years. Hospitalisations were recorded from discharge letters, medical records, and patient interviews. The association of atrial fibrillation, anticoagulation, and time-in-therapeutic range of vitamin K antagonist treatment with hospitalisations was analysed using negative binomial regression. RESULTS: Out of 625 patients, 238 (38.1%) had atrial fibrillation. Median number of hospitalisations per patient was 3.0 (1.0-5.0). Incidence rate of hospitalisation was 1.7 per patient-year in all and 1.9 in atrial fibrillation patients, median duration per hospitalisation was 7.9 (4.8-12.9) and 8.8 (5.7-13.3) days, respectively. Most frequent reasons for hospitalisation were vascular access complication/intervention (11.7%) and infection/fever (11.4%), while bleeding events comprised 6.0% of all hospitalisations. Atrial fibrillation patients had 27% higher risk of hospitalisation than patients without atrial fibrillation (incidence rate ratio [IRR] 1.27, 95% confidence interval [CI] 1.10-1.47). In atrial fibrillation patients, anticoagulation (enoxaparin or phenprocoumon, 41.6% of AF patients) was associated with increased risk of all-cause (IRR 1.38, 95%CI 1.14-1.69) and bleeding-related hospitalisation (IRR 1.96, 95%CI 1.06-3.63). There was no association between anticoagulation and stroke-related hospitalisation. In atrial fibrillation patients on phenprocoumon, increasing time-in-therapeutic range was associated with decreased risk of all-cause (IRR 0.35, 95%CI 0.14-0.87), but not bleeding-related hospitalisation (IRR 0.13, 95%CI 0.01-1.38). CONCLUSION: In haemodialysis patients, presence of atrial fibrillation and, among those with atrial fibrillation, anticoagulation were associated with higher risk of all-cause hospitalisation, including bleeding-related hospitalisation in the latter. Increasing time-in-therapeutic range in patients on vitamin K antagonist treatment was associated with decreased risk of all-cause, but not bleeding-related hospitalisation.

SARS-CoV-2-related mortality and treatment delays for cancer patients in Austria : Findings of a multicentric nationwide study.

BACKGROUND: Cancer patients infected with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have an increased risk of mortality. Here, we investigated predictive factors for coronavirus disease 2019 (COVID-19) associated mortality in patients with neoplastic diseases treated throughout Austria. METHODS: In this multicentric nationwide cohort study, data on patients with active or previous malignant diseases and SARS-CoV­2 infections diagnosed between 13 March 2020 and 06 April 2021 were collected. Collected data included the stage of the malignant disease and outcome parameters 30 days after the diagnosis of SARS-CoV­2 infection. RESULTS: The cohort consisted of 230 individuals of which 75 (32.6%) patients were diagnosed with hematologic malignancies and 155 (67.4%) with solid tumors. At a median follow-up of 31 days after COVID-19 diagnosis, 38 (16.5%) patients had died due to COVID-19. Compared to survivors, patients who died were older (62.4 vs. 71.4 years, p < 0.001) and had a higher ECOG performance status (0.7 vs. 2.43, p < 0.001). Furthermore, higher neutrophil counts (64.9% vs. 73.8%, p = 0.03), lower lymphocyte counts (21.4% vs. 14%, p = 0.006) and lower albumin levels (32.5 g/l vs. 21.6 g/l, p < 0.001) were observed to be independent risk factors for adverse outcomes. No association between mortality and systemic antineoplastic therapy was found (p > 0.05). In 60.6% of the patients, therapy was postponed due to quarantine requirements or hospital admission. CONCLUSION: Mortality of Austrian cancer patients infected with SARS-CoV­2 is comparable to that of other countries. Furthermore, risk factors associated with higher mortality were evident and similar to the general population. Treatment delays were frequently observed.

Bleeding Risk Assessment in End-Stage Kidney Disease: Validation of Existing Risk Scores and Evaluation of a Machine Learning-Based Approach.

BACKGROUND: Patients with end-stage kidney disease (ESKD) on hemodialysis (HD) are at increased risk for bleeding. However, despite relevant clinical implications regarding dialysis modalities or anticoagulation, no bleeding risk assessment strategy has been established in this challenging population. METHODS: Analyses on bleeding risk assessment models were performed in the population-based Vienna InVestigation of Atrial fibrillation and thromboemboLism in patients on hemoDialysIs (VIVALDI) study including 625 patients. In this cohort study, patients were prospectively followed for a median observation period of 3.5 years for the occurrence of major bleeding. First, performances of existing bleeding risk scores (i.e., HAS-BLED, HEMORR2HAGES, ATRIA, and four others) were evaluated in terms of discrimination and calibration. Second, four machine learning-based prediction models that included clinical, dialysis-specific, and laboratory parameters were developed and tested using Monte Carlo cross-validation. RESULTS: Of 625 patients (median age: 66 years, 37% women), 89 (14.2%) developed major bleeding, with a 1-year, 2-year, and 3-year cumulative incidence of 6.1% (95% confidence interval [CI]: 4.2-8.0), 10.3% (95% CI: 8.0-12.8), and 13.5% (95% CI: 10.8-16.2), respectively. C-statistics of the seven contemporary bleeding risk scores ranged between 0.54 and 0.59 indicating poor discriminatory performance. The HAS-BLED score showed the highest C-statistic of 0.59 (95% CI: 0.53-0.66). Similarly, all four machine learning-based predictions models performed poorly in internal validation (C-statistics ranging from 0.49 to 0.55). CONCLUSION: Existing bleeding risk scores and a machine learning approach including common clinical parameters fail to assist in bleeding risk prediction of patients on HD. Therefore, new approaches, including novel biomarkers, to improve bleeding risk prediction in patients on HD are needed.

Influence of TP53 Mutation on Survival of Diffuse Large B-Cell Lymphoma in the CAR T-Cell Era.

Refractory/relapsed diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The clinical behavior and genetic landscape of DLBCL is heterogeneous and still not fully understood. TP53 mutations in DLBCL have been identified as markers of poor prognosis and are often associated with therapeutic resistance. Chimeric antigen receptor T-cell therapy is an innovative therapeutic concept and represents a game-changing therapeutic option by supporting the patient's own immune system to kill the tumor cells. We investigated the impact of TP53 mutations on the overall survival of refractory/relapsed DLBCL patients treated with comparable numbers of therapy lines. The minimum number of therapy lines was 2 (median 4), including either anti-CD19 CAR T-cell therapy or conventional salvage therapy. A total of 170 patients with DLBCL and high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements (DHL/THL), diagnosed and treated in our hospital between 2000 and 2021, were included. Twenty-nine of them received CAR T-cell therapy. TP53 mutations were found in 10/29 (35%) and 31/141 (22%) of patients in the CAR T-cell and conventional groups, respectively. Among the 141 patients not treated with CAR T cells, TP53 mutation was an independent prognostic factor for overall survival (OS) (median 12 months with TP53 vs. not reached without TP53 mutation, p < 0.005), but in the CAR T cell treated group, this significance could not be shown (median OS 30 vs. 120 months, p = 0.263). The findings from this monocentric retrospective study indicate that TP53 mutation status does not seem to affect outcomes in DLBCL patients treated with CAR T-cell therapy. Detailed evaluation in large cohorts is warranted.

Anticoagulation use and the risk of stroke and major bleeding in patients on hemodialysis: From the VIVALDI, a population-based prospective cohort study.

BACKGROUND: Evidence supporting the use of anticoagulation for the prevention of stroke and thromboembolism in patients with kidney failure on hemodialysis (HD) and atrial fibrillation (AF) is limited. We prospectively assessed the incidences of stroke and major bleeding, as well as anticoagulation strategies in patients on HD with AF. METHODS: We recruited 625 prevalent HD patients into a population-based observational cohort study. The primary prospective outcomes were thromboembolic events (stroke, transient ischemic attack, systemic embolism) and major bleeding. Secondary outcomes included a composite of thromboembolic events, major bleeding, and cardiovascular death to determine net clinical harm. RESULTS: A total of 238 patients (38.1%) had AF, 165 (26.4%) already at baseline and 73 (15.9%) developed AF during a median follow up of 870 days. Forty (6.4%) thromboembolic events and 89 (14.2%) major bleedings occurred. Overall, 256 patients died (41.0%). In AF patients, use of vitamin K antagonists (VKAs) in 61 patients (25.6%) was not significantly associated with reduced risk of the primary thromboembolic outcome (subdistribution hazard ratio [SHR] 1.41 adjusted for age, sex, congestive heart failure, hypertension, stroke/transient ischemic attack/thromboembolism, vascular disease, and diabetes history score and antiplatelet co-medication (95% CI, 0.49-4.07), but with increased risk of major bleeding (SHR: 2.28; 95% CI, 1.09-4.79) compared with AF patients without anticoagulation (N = 139, 58.4%). Use of VKAs was associated with net clinical harm (adjusted SHR: 2.07; 95% CI, 1.25-3.42). CONCLUSIONS: Although the nonrandomized nature of the study is prone to bias, anticoagulation with VKAs was not associated with decreased thromboembolic risk, but rather with increased risk of major bleeding and may be net harmful to patients with AF on HD.

Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer-a nationwide analysis.

AIMS: An interrelation between cancer and thrombosis is known, but population-based studies on the risk of both arterial thromboembolism (ATE) and venous thromboembolism (VTE) have not been performed. METHODS AND RESULTS: International Classification of Disease 10th Revision (ICD-10) diagnosis codes of all publicly insured persons in Austria (0-90 years) were extracted from the Austrian Association of Social Security Providers dataset covering the years 2006-07 (n = 8 306 244). Patients with a history of cancer or active cancer were defined as having at least one ICD-10 'C' diagnosis code, and patients with ATE and/or VTE as having at least one of I21/I24 (myocardial infarction), I63/I64 (stroke), I74 (arterial embolism), and I26/I80/I82 (venous thromboembolism) diagnosis code. Among 158 675 people with cancer, 8559 (5.4%) had an ATE diagnosis code and 7244 (4.6%) a VTE diagnosis code. In contrast, among 8 147 569 people without cancer, 69 381 (0.9%) had an ATE diagnosis code and 29 307 (0.4%) a VTE diagnosis code. This corresponds to age-stratified random-effects relative risks (RR) of 6.88 [95% confidence interval (CI) 4.81-9.84] for ATE and 14.91 (95% CI 8.90-24.95) for VTE. ATE proportion was highest in patients with urinary tract malignancies (RR: 7.16 [6.74-7.61]) and lowest in patients with endocrine cancer (RR: 2.49 [2.00-3.10]). The corresponding VTE proportion was highest in cancer of the mesothelium/soft tissue (RR: 19.35 [17.44-21.47]) and lowest in oropharyngeal cancer (RR: 6.62 [5.61-7.81]). CONCLUSION: The RR of both ATE and VTE are significantly higher in persons with cancer. Our population-level meta-data indicate a strong association between cancer, ATE and VTE, and support the concept of shared risk factors and pathobiology between these diseases.Relative risk of ATE and VTE in persons with a cancer diagnosis code versus persons without a cancer diagnosis code.

Growth differentiation factor-15 predicts major adverse cardiac events and all-cause mortality in patients with atrial fibrillation.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) has recently been described as a potential biomarker for predicting risk of mortality and cardiovascular events in patients with atrial fibrillation (AF) but requires validation in clinical practice. METHODS: The study population consisted of 362 patients (mean age: 71 years, 37% women) with non-valvular AF included in a prospective cohort study. Relationship of GDF-15 with all-cause mortality and major adverse cardiac events (MACE) was analyzed using Cox regression. Survival analysis stratified by GDF-15 was based on national death records, while MACE was recorded at personal follow-up. Further, we evaluated the recently developed GDF-15 based prognostic score towards prediction of all-cause mortality (ABC-death score). RESULTS: Over a median observation period of 4.3 years, 81 (23.3%) patients died, and over a median personal follow-up of 316 days 47 MACE occurred. GDF-15 was independently associated with all-cause mortality (adjusted HR per double increase 2.33, 95%CI 1.74-3.13) and MACE (adjusted HR per double increase 2.33, 95%CI 1.60-3.39). GDF-15 levels, measured at follow-up, were similarly associated with mortality, and longitudinal measurements of GDF-15 did not significantly differ. Six-year survival probability of patients above vs. below the median GDF-15 level was 44% (95%CI 34-57) and 84% (95%CI 76-93), respectively. The ABC-death score revealed a C-statistic of 0.80. CONCLUSION: GDF-15 predicts risk of all-cause mortality and MACE in patients with non-valvular AF. Further, the ABC-death score showed good predictive accuracy in a "real-world" cohort. Therefore, introduction of GDF-15 into clinical practice would enhance risk prediction of morbidity and mortality in AF patients.

Pulmonary embolism during the COVID-19 pandemic: Decline in diagnostic procedures and incidence at a university hospital.

BACKGROUND: The COVID-19 pandemic has focused medical attention on treating affected patients and protecting others from infection. However, concerns have been raised regarding the pandemic´s impact and associated containment measures (eg curfew, lockdown) on non-coronavirus disease 2019 (COVID-19)-related acute medical diseases. OBJECTIVES: To investigate changes in the incidence of pulmonary embolism (PE) during the COVID-19 pandemic compared to the period before the pandemic and reference periods in previous years. METHODS: In this single-center study, we explored all diagnostic imaging tests performed for suspected PE between weeks 1 and 17 of the years 2018, 2019, and 2020. Incidence of PE (ie, primary outcome) was analyzed. Secondary outcomes included number of imaging tests for suspected PE. RESULTS: Compared to weeks 1 to 11, 2020, an abrupt decline in PE diagnosis (mean weekly rate, 5.2; 95% confidence interval [CI], 3.8-6.6 vs 1.8; 95% CI, 0.0-3.6) and imaging tests (mean weekly rate, 32.5; 95% CI, 27.5-37.6 vs. 17.3; 95% CI, 11.6-23.1) was observed from week 12, with beginning of the containment measures and public lockdown in Austria. Compared to weeks 12 to 17 of 2018 and 2019, PE incidence and imaging tests were similarly decreased from 5.3 (95% CI, 3.6-7.1) to 1.8 (95% CI, 0.0-3.6) and 31.5 (95% CI, 27.1-35.9) to 17.3 (95% CI, 11.6-23.1), respectively. The median simplified pulmonary embolism severity index (sPESI) score of PE patients during the pandemic was higher than in all other PE patients (3; interquartile range, 1-3 vs 1; interquartile range, 0-2; P = .002). CONCLUSION: Our study demonstrates that the COVID-19 pandemic has an impact on non-COVID-19-related acute diseases as shown by the decline in incidence of PE and imaging procedures for diagnostic workup. Further studies from other hospitals are needed to confirm our findings.

Antithrombotic agents for primary and secondary prevention of cardiovascular events in patients with end-stage renal disease on chronic hemodialysis.

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.

Influence of blood group, von Willebrand factor levels, and age on factor VIII levels in non-severe haemophilia A.

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.

Ex vivo properties of plasma clot formation and lysis in patients with cancer at risk for venous thromboembolism, arterial thrombosis, and death.

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.