Risk assessment tools for bleeding in patients with unprovoked venous thromboembolism: an analysis of the PLATO-VTE study.

BACKGROUND: Guidelines suggest indefinite anticoagulation after unprovoked venous thromboembolism (VTE) unless the bleeding risk is high, yet there is no consistent guidance on assessing bleeding risk. This study aimed to evaluate the performance of five bleeding risk tools (RIETE, VTE-BLEED, CHAP, VTE-PREDICT, and ABC-bleeding). METHODS: PLATO-VTE, a prospective cohort study, included patients aged ≥40 years with a first unprovoked VTE. Risk estimates were calculated at VTE diagnosis and after 3 months of treatment. Primary outcome was clinically relevant bleeding, as per ISTH criteria, during 24-month follow-up. Discrimination was assessed by the area under the receiver operating characteristic curve (AUROC). Patients were classified as having a 'high-risk' and 'non-high-risk' of bleeding according to predefined thresholds; bleeding risk in both groups was compared by hazard ratios. RESULTS: Of 514 patients, 38 (7.4%) had an on-treatment bleeding. AUROCs were 0.58 (95%CI, 0.48-0.68) for ABC-bleeding, 0.56 (95%CI, 0.46-0.66) for RIETE, 0.53 (95%CI, 0.43-0.64) for CHAP, 0.50 (95%CI, 0.41-0.59) for VTE-BLEED, and 0.50 (95%CI, 0.40-0.60) for VTE-PREDICT. The proportion of high-risk patients ranged from 1.4% with RIETE to 36.9% with VTE-BLEED. The bleeding incidence in the high-risk groups ranged from 0% with RIETE to 13.0% with ABC-bleeding, and in the non-high-risk groups from 7.7% with ABC-bleeding to 9.6% with RIETE. Hazard ratios ranged from 0.93 (95%CI, 0.46-1.9) for VTE-BLEED to 1.67 (95%CI, 0.86-3.2) for ABC-bleeding. Recalibration at 3-month follow-up did not alter the results. CONCLUSIONS: In this cohort, discrimination of currently available bleeding risk tools was poor. These data do not support their use in patients with unprovoked VTE.

Specimen type validation and establishment of normal cytokine reference intervals in cerebrospinal fluid.

Cerebrospinal fluid (CSF) is a critical body fluid to examine in attempts to discover potential biomarkers for neuroinflammatory and other disorders of the central nervous system (CNS). Serum and/or plasma cytokine levels have been associated with a variety of inflammatory conditions, and some have been shown to be actionable therapeutic targets. Less is known, however, about cytokine levels in CSF. Serum and plasma cytokine testing is widely available in clinical and research laboratories, but cytokine testing in CSF is extremely limited and if performed, accompanied by a disclaimer that it is an unvalidated specimen type. In this study, we validate CSF as a suitable specimen type and determine normal reference intervals for multiple cytokines as well as a soluble cytokine receptor. CSF was validated as a specimen type for testing using a laboratory developed multiplexed cytokine assay previously validated to measure 13 cytokines/markers in serum and plasma. Performance parameters including specimen dilution, specimen interference, linearity and precision were examined. Reference intervals were established using 197 normal and control CSF specimens by non-parametric quantile-based methods. CSF cytokine analysis demonstrated within and between run precision of <10% and < 20% CV, respectively and linearity of ±15% for all analytes throughout the analytical measurement range of the assay. Reference intervals for the 13 cytokines/markers were established from 197 normal and control CSF specimens (78 Male; mean 44.8 y ± 21.7 SD, 119 Female; mean 42.8 y ± 20.3 SD). Cytokine concentrations in CSF from normal donors and controls were less than the lower limit of quantitation of our assay for 6 of the 13 measured cytokines/markers. The chemokine IL8 demonstrated the highest concentration of all analytes measured. CSF demonstrated acceptable performance as a specimen type in our multiplexed cytokine assay. By validating CSF as a specimen type and establishing normal reference intervals for cytokine concentrations in CSF, their potential as biomarkers for infectious, autoimmune and other inflammatory CNS disorders can be more appropriately investigated.

Targeting the Plasmodium falciparum UCHL3 ubiquitin hydrolase using chemically constrained peptides.

The ubiquitin-proteasome system is essential to all eukaryotes and has been shown to be critical to parasite survival as well, including Plasmodium falciparum, the causative agent of the deadliest form of malarial disease. Despite the central role of the ubiquitin-proteasome pathway to parasite viability across its entire life-cycle, specific inhibitors targeting the individual enzymes mediating ubiquitin attachment and removal do not currently exist. The ability to disrupt P. falciparum growth at multiple developmental stages is particularly attractive as this could potentially prevent both disease pathology, caused by asexually dividing parasites, as well as transmission which is mediated by sexually differentiated parasites. The deubiquitinating enzyme PfUCHL3 is an essential protein, transcribed across both human and mosquito developmental stages. PfUCHL3 is considered hard to drug by conventional methods given the high level of homology of its active site to human UCHL3 as well as to other UCH domain enzymes. Here, we apply the RaPID mRNA display technology and identify constrained peptides capable of binding to PfUCHL3 with nanomolar affinities. The two lead peptides were found to selectively inhibit the deubiquitinase activity of PfUCHL3 versus HsUCHL3. NMR spectroscopy revealed that the peptides do not act by binding to the active site but instead block binding of the ubiquitin substrate. We demonstrate that this approach can be used to target essential protein-protein interactions within the Plasmodium ubiquitin pathway, enabling the application of chemically constrained peptides as a novel class of antimalarial therapeutics.

Increased Prevalence of Antibodies to Hepatitis E Virus in Patients with Neurocysticercosis.

We explored the association between serological status for hepatitis E and neurocysticercosis (NCC) in neurologic patients attending a national neurological referral center in Lima, Perú, between the years 2008 and 2012. Anti-hepatitis E antibodies were evaluated in patients with and without NCC, and a control group of rural general population. Anti-hepatitis E IgG was found in 23.8% of patients with NCC, compared with 14.3% in subjects without NCC from a general rural population (P = 0.023) and 14.4% in subjects with neurological complaints without NCC (P = 0.027). Seropositive patients had a median age of 44 years compared with 30 years in seronegative patients (P <0.001). No significant differences in sex, region of residence, or liver enzyme values were found. Seropositivity to hepatitis E was frequent in this Peruvian population and higher in patients with NCC, suggesting shared common routes of infection.

Structure-guided aminoacylation and assembly of chimeric RNAs.

Coded ribosomal peptide synthesis could not have evolved unless its sequence and amino acid specific aminoacylated tRNA substrates already existed. We therefore wondered whether aminoacylated RNAs might have served some primordial function prior to their role in protein synthesis. Here we show that specific RNA sequences can be nonenzymatically aminoacylated and ligated to produce amino acid-bridged stem-loop RNAs. We used deep sequencing to identify RNAs that undergo highly efficient glycine aminoacylation followed by loop-closing ligation. The crystal structure of one such glycine-bridged RNA hairpin reveals a compact internally stabilized structure with the same eponymous T-loop architecture found in modern tRNA. We demonstrate that the T-loop assisted amino acid bridging of RNA oligonucleotides enables the rapid template-free assembly of a chimeric version of an aminoacyl-RNA synthetase ribozyme. We suggest that the primordial assembly of such chimeric ribozymes would have allowed the greater functionality of amino acids to contribute to enhanced ribozyme catalysis, providing a driving force for the evolution of sequence and amino acid specific aminoacyl-RNA synthetase enzymes prior to their role in protein synthesis.

From Functional Fatty Acids to Potent and Selective Natural-Product-Inspired Mimetics via Conformational Profiling.

Fatty acids play important signaling roles in biology, albeit typically lacking potency or selectivity, due to their substantial conformational flexibility. While being recognized as having properties of potentially great value as therapeutics, it is often the case that the functionally relevant conformation of the natural fatty acid is not known, thereby complicating efforts to develop natural-product-inspired ligands that have similar functional properties along with enhanced potency and selectivity profiles. In other words, without structural information associated with a particular functional relationship and the hopelessly unbiased conformational preferences of the endogenous ligand, one is molecularly ill-informed regarding the precise ligand-receptor interactions that play a role in driving the biological activity of interest. To address this problem, a molecular strategy to query the relevance of distinct subpopulations of fatty acid conformers has been established through "conformational profiling", a process whereby a unique collection of chiral and conformationally constrained fatty acids is employed to deconvolute beneficial structural features that impart natural-product-inspired function. Using oleic acid as an example because it is known to engage a variety of receptors, including GPR40, GPR120, and TLX, a 24-membered collection of mimetics was designed and synthesized. It was then demonstrated that this collection contained members that have enhanced potency and selectivity profiles, with some being clearly biased for engagement of the GPCRs GPR40 and GPR120 while others were identified as potent and selective modulators of the nuclear receptor TLX. A chemical synthesis strategy that exploited the power of modern technology for stereoselective synthesis was critical to achieving success, establishing a common sequence of bond-forming reactions to access a disparate collection of chiral mimetics, whose conformational preferences are impacted by the nature of stereodefined moieties differentially positioned about the C18 skeleton of the parent fatty acid. Overall, this study establishes a foundation to fuel future programs aimed at developing natural-product-inspired fatty acid mimetics as valuable tools in chemical biology and potential therapeutic leads.

Doxorubicin Exposure and Breast Cancer Risk in Survivors of Adolescent and Adult Hodgkin Lymphoma.

PURPOSE: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Studies in childhood cancer survivors have shown that doxorubicin exposure may also increase BC risk. Although doxorubicin is the cornerstone of HL chemotherapy, the association between doxorubicin and BC risk has not been examined in HL survivors treated at adult ages. METHODS: We assessed BC risk in a cohort of 1,964 female 5-year HL survivors, treated at age 15-50 years in 20 Dutch hospitals between 1975 and 2008. We calculated standardized incidence ratios, absolute excess risks, and cumulative incidences. Doxorubicin exposure was analyzed using multivariable Cox regression analyses. RESULTS: After a median follow-up of 21.6 years (IQR, 15.8-27.1 years), 252 women had developed invasive BC or ductal carcinoma in situ. The 30-year cumulative incidence was 20.8% (95% CI, 18.2 to 23.4). Survivors treated with a cumulative doxorubicin dose of >200 mg/m2 had a 1.5-fold increased BC risk (95% CI, 1.08 to 2.1), compared with survivors not treated with doxorubicin. BC risk increased 1.18-fold (95% CI, 1.05 to 1.32) per additional 100 mg/m2 doxorubicin (Ptrend = .004). The risk increase associated with doxorubicin (yes v no) was not modified by age at first treatment (hazard ratio [HR]age <21 years, 1.5 [95% CI, 0.9 to 2.6]; HRage ≥21 years, 1.3 [95% CI, 0.9 to 1.9) or chest RT (HRwithout mantle/axillary field RT, 1.9 [95% CI, 1.06 to 3.3]; HRwith mantle/axillary field RT, 1.2 [95% CI, 0.8 to 1.8]). CONCLUSION: This study shows that treatment with doxorubicin is associated with increased BC risk in both adolescent and adult HL survivors. Our results have implications for BC surveillance guidelines for HL survivors and treatment strategies for patients with newly diagnosed HL.

Disentangling differing relationships between internalizing disorders and alcohol use.

Both internalizing disorders and alcohol use have dramatic, wide-spread implications for global health. Previous work has established common phenotypic comorbidity among these disorders, as well as shared genetic variation underlying them both. We used genomic structural equation modeling to investigate the shared genetics of internalizing, externalizing, and alcohol use traits, as well as to explore whether specific domains of internalizing symptoms mediate the contrasting relationships with problematic alcohol use compared to alcohol consumption. We also examined patterns of genetic correlations between similar traits within additional Finnish and East Asian ancestry groups. When the shared genetic influence of externalizing psychopathology was accounted for, the genetic effect of internalizing traits on alcohol use was reduced, suggesting the important role of common genetic factors underlying multiple psychiatric disorders and their genetic influences on comorbidity of internalizing and alcohol use traits. Individual internalizing domains had contrasting effects on frequency of alcohol consumption, which demonstrate the complex system of pleiotropy that exists, even within similar disorders, and can be missed when evaluating only relationships among formal diagnoses. Future work must consider the broad effects of shared psychopathology along with the fine-scale effects of heterogeneity within disorders to more fully understand the biology underlying complex traits.

In Vitro and In Vivo Assessment of the Infection Resistance and Biocompatibility of Small-Molecule-Modified Polyurethane Biomaterials.

Bacterial intracellular nucleotide second messenger signaling is involved in biofilm formation and regulates biofilm development. Interference with the bacterial nucleotide second messenger signaling provides a novel approach to control biofilm formation and limit microbial infection in medical devices. In this study, we tethered small-molecule derivatives of 4-arylazo-3,5-diamino-1H-pyrazole on polyurethane biomaterial surfaces and measured the biofilm resistance and initial biocompatibility of modified biomaterials in in vitro and in vivo settings. Results showed that small-molecule-modified surfaces significantly reduced the Staphylococcal epidermidis biofilm formation compared to unmodified surfaces and decreased the nucleotide levels of c-di-AMP in biofilm cells, suggesting that the tethered small molecules interfere with intracellular nucleotide signaling and inhibit biofilm formation. The hemocompatibility assay showed that the modified polyurethane films did not induce platelet activation or red blood cell hemolysis but significantly reduced plasma coagulation and platelet adhesion. The cytocompatibility assay with fibroblast cells showed that small-molecule-modified surfaces were noncytotoxic and cells appeared to be proliferating and growing on modified surfaces. In a 7-day subcutaneous infection rat model, the polymer samples were implanted in Wistar rats and inoculated with bacteria or PBS. Results show that modified polyurethane significantly reduced bacteria by ∼2.5 log units over unmodified films, and the modified polymers did not lead to additional irritation/toxicity to the animal tissues. Taken together, the results demonstrated that small molecules tethered on polymer surfaces remain active, and the modified polymers are biocompatible and resistant to microbial infection in vitro and in vivo.

Specific dietary fibers prevent heavy metal disruption of the human gut microbiota in vitro.

Heavy metal exposure is a growing concern due to its adverse effects on human health, including the disruption of gut microbiota composition and function. Dietary fibers have been shown to positively impact the gut microbiota and could mitigate some of the heavy metal negative effects. This study aimed to investigate the effects of different heavy metals (As, Cd and Hg in different concentrations) on gut microbiota in the presence and absence of different dietary fibers that included fructooligosaccharides, pectin, resistant starch, and wheat bran. We observed that whereas heavy metals impaired fiber fermentation outcomes for some fiber types, the presence of fibers generally protected gut microbial communities from heavy metal-induced changes, especially for As and Cd. Notably, the protective effects varied depending on fiber types, and heavy metal type and concentration and were overall stronger for wheat bran and pectin than other fiber types. Our findings suggest that dietary fibers play a role in mitigating the adverse effects of heavy metal exposure on gut microbiota health and may have implications for the development of dietary interventions to reduce dysbiosis associated with heavy metal exposure. Moreover, fiber-type specific outcomes highlight the importance of evidence-based selection of prebiotic dietary fibers to mitigate heavy metal toxicity to the gut microbiota.

Distinct peripheral T-cell and NK-cell profiles in HGBL-MYC/BCL2 vs patients with DLBCL NOS.

ABSTRACT: Patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBL-MYC/BCL2) respond poorly to immunochemotherapy compared with patients with diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) without a MYC rearrangement. This suggests a negative impact of lymphoma-intrinsic MYC on the immune system. To investigate this, we compared circulating T cells and natural killer (NK) cells of patients with HGBL-MYC/BCL2 (n = 66), patients with DLBCL NOS (n = 53), and age-matched healthy donors (HDs; n = 16) by flow cytometry and performed proliferation, cytokine production, and cytotoxicity assays. Compared with HDs, both lymphoma subtypes displayed similar frequencies of CD8+ T cells but decreased CD4+ T cells. Regulatory T-cell (Treg) frequencies were reduced only in patients with DLBCL NOS. Activated (HLA-DR+/CD38+) T cells, PD-1+CD4+ T cells, and PD-1+Tregs were increased in both lymphoma subtypes, but PD-1+CD8+ T cells were increased only in HGBL-MYC/BCL2. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of senescent T cells than HDs. Functional assays showed no overt differences between both lymphoma groups and HDs. Deeper analyses revealed that PD-1+ T cells of patients with HGBL-MYC/BCL2 were exhausted with impaired cytokine production and degranulation. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of NK cells expressing inhibiting receptor NKG2A. Both lymphoma subtypes exhibited lower TIM-3+- and DNAM-1+-expressing NK cells. Although NK cells of patients with HGBL-MYC/BCL2 showed less degranulation, they were not defective in cytotoxicity. In conclusion, our results demonstrate an increased exhaustion in circulating T cells of patients with HGBL-MYC/BCL2. Nonetheless, the overall intact peripheral T-cell and NK-cell functions in these patients emphasize the importance of investigating potential immune evasion in the microenvironment of MYC-rearranged lymphomas.

Clinical predictive value of renalase in post-ERCP pancreatitis.

BACKGROUND AND AIMS: Plasma levels of renalase decrease in acute experimental pancreatitis. We aimed to determine if decreases in plasma renalase levels after ERCP predict the occurrence of post-ERCP pancreatitis (PEP). METHODS: In this prospective cohort study conducted at a tertiary hospital, plasma renalase was determined before ERCP (baseline) and at 30 and 60 minutes after ERCP. Native renalase levels, acidified renalase, and native-to-acidified renalase proportions were analyzed over time using a longitudinal regression model. RESULTS: Among 273 patients, 31 developed PEP. Only 1 PEP patient had a baseline native renalase >6.0 µg/mL, whereas 38 of 242 without PEP had a native renalase > 6.0 µg/mL, indicating a sensitivity of 97% (30/31) and specificity of 16% (38/242) in predicting PEP. Longitudinal models did not show differences over time between groups. CONCLUSIONS: Baseline native renalase levels are very sensitive for predicting PEP. Further studies are needed to determine the potential clinical role of renalase in predicting and preventing PEP.

Cross-sectional and longitudinal assessment of cognitive development in Williams syndrome.

Williams syndrome (WS) is a rare genetic syndrome. As with all rare syndromes, obtaining adequately powered sample sizes is a challenge. Here we present legacy data from seven UK labs, enabling the characterisation of cross-sectional and longitudinal developmental trajectories of verbal and non-verbal development in the largest sample of individuals with WS to-date. In Study 1, we report cross-sectional data between N = 102 and N = 209 children and adults with WS on measures of verbal and non-verbal ability. In Study 2, we report longitudinal data from N = 17 to N = 54 children and adults with WS who had been tested on at least three timepoints on these measures. Data support the WS characteristic cognitive profile of stronger verbal than non-verbal ability, and shallow developmental progression for both domains. Both cross-sectional and longitudinal data demonstrate steeper rates of development in the child participants than the adolescent and adults in our sample. Cross-sectional data indicate steeper development in verbal than non-verbal ability, and that individual differences in the discrepancy between verbal and non-verbal ability are largely accounted for by level of intellectual functioning. A diverging developmental discrepancy between verbal and non-verbal ability, whilst marginal, is not mirrored statistically in the longitudinal data. Cross-sectional and longitudinal data are discussed with reference to validating cross-sectional developmental patterns using longitudinal data and the importance of individual differences in understanding developmental progression.

The dimensional structure of internalizing psychopathology: Relation to diagnostic categories.

Recent approaches aim to represent the dimensional structure of psychopathology, but relatively little research has rigorously tested sub-dimensions within internalizing psychopathology. This study tests pre-registered models of the dimensional structure of internalizing psychopathology, and their relations with current and lifetime depressive and anxiety disorders diagnostic data, in adult samples harmonized across three sites (n=427). Across S-1 bifactor and hierarchical models, we found converging evidence for both general and specific internalizing dimensions. Depression, generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic attacks were all associated with a general internalizing factor that we posit primarily represents motivational anhedonia. GAD was also associated with a specific anxious apprehension factor, and SAD with specific anxious apprehension and low positive affect factors. We suggest that dimensional approaches capturing shared and specific internalizing symptom facets more accurately describe the structure of internalizing psychopathology and provide useful alternatives to categorical diagnoses to advance clinical science.

Novel insights into weight loss: acupuncture combined with a very low-carbohydrate diet-a Swiss experience.

OBJECTIVE: The objective of this study was to assess the effects of an acupuncture-diet program for treatment of overweight and obesity. METHODS: The program consisted of weekly acupuncture sessions combined with a very low-carbohydrate diet in patients with a body mass index (BMI) of 25 kg/m2 or above. Data were collected retrospectively between 2002 and 2021 in seven clinics in Switzerland through automated data extraction of existing medical records. The treatments described are standard care at the facilities where they took place. RESULTS: A total of 11,233 patients were included. In those with a BMI of 25 kg/m2 or above, a positive effect on body weight was noted with a peak average body weight loss of approximately 17.5 kg reached after 7 months. Long-term stabilization was at about 15.5 kg after 18 months. Significant male-female differences (p < 0.01) were observed with women losing less weight. Differences were also noted between overweight, obese and extremely obese patients suggesting a BMI-dependent effect. Maximum weight loss of patients with BMI of 35 kg/m2 or above was 29.8 ± 12 kg, while it was 18.8 ± 8 kg for obese patients (BMI = 30-34.9 kg/m2) and 12 ± 7 kg for overweight patients (BMI = 25-29.9 kg/m2), reflecting a significant overall difference between groups (p < 0.01). Compliance to the protocol by patients and physicians seemed to be another differentiating factor; more adherent patients appeared to lose more weight and preserve body weight loss better over time. CONCLUSION: Although this study lacked a control group and was retrospective and observational in nature, a program of acupuncture combined with a very low-carbohydrate diet appeared to be effective at inducing weight loss among obese patients. The observed weight reduction in this retrospective chart review represents a good starting point for further investigation of this approach via a comparative evaluation.

Impact of mild thrombocytopenia on bleeding and recurrent thrombosis in cancer.

Thrombocytopenia occurs frequently in patients with cancer-associated thrombosis (CAT), however prospective evaluation of clinical outcomes following randomization to anticoagulants is limited. The HOKUSAI VTE Cancer study was a randomized, open-label, non-inferiority, phase III trial comparing dalteparin with edoxaban in CAT patients. This post hoc analysis of Hokusai VTE Cancer Study was performed to compare outcomes in patients with platelet count ≤100 K/µL at one or more specified time points (baseline, 1-month, or 3-month) versus those without thrombocytopenia. Cumulative incidences at 180 days were calculated with death as a competing risk. The primary outcome was major bleeding; secondary outcomes were clinically relevant non-major bleeding (CRNMB), recurrent thrombosis, and survival. The analysis included 1,045 patients with primarily solid tumor malignancies (89%), median age 65 years, and 52% male. The thrombocytopenia group comprised 9.6% (N=101) of the cohort and relative to the non-thrombocytopenia cohort (N=944), experienced significantly higher major bleeding (9.0% vs. 4.0%, sub-distribution hazard ratio (SHR) 2.4, P=0.02) and CRNMB (17.9% vs. 9.6%, SHR 2.0, P=0.01). Thrombocytopenia did not impact recurrent VTE (9.8% vs. 7.4%, SHR 1.3, P=0.37) nor overall mortality (21.8% vs. 26.0%, HR 0.9, P=0.48). Major bleeding was higher in patients with thrombocytopenia and gastrointestinal malignancies receiving edoxaban versus dalteparin (16.8% vs 0, p.

Impact of venous thromboembolism on the mortality in patients with cancer: a population-based cohort study.

Background: Despite recent improvements in the treatment of cancer, little is known about the long-term survival in patients with cancer and venous thromboembolism. We aimed to examine the five-year mortality of venous thromboembolism in cancer patients in a large population-based cohort study. Methods: Using Danish healthcare registries from 1995 to 2020, we obtained data on cancer patients with venous thromboembolism and comparison cohorts of cancer patients without venous thromboembolism, matched in terms of cancer type, age, sex, and year of cancer diagnosis, and adjusted for level of comorbidity and frailty using the Charlson Comorbidity Index Score and Hospital Frailty Risk Score, marital status, use of selected medications, and recent surgery (<90 days). Findings: During the study period, 886,536 patients were diagnosed with cancer. Of 1882 cancer patients diagnosed at the time of their venous thromboembolism, 44.4% (835/1882) had distant metastases. In this cohort, the one- and five-year mortality cumulative incidences were 68% (1284/1882) and 84% (1578/1882), respectively, in contrast to 38% (2135/5549) and 67% (3653/5549) in the comparison cohort. The mortality rate ratio was 4.34 (95% confidence interval [CI], 3.95-4.78) for the first year of follow-up and 3.44 (95% CI 3.17-3.73) for the five-year follow-up period. Of the 23,366 patients diagnosed with venous thromboembolism after cancer diagnosis, 18% (4183/23,366) had distant metastases at the time of cancer diagnosis. The cumulative incidence of death at one year was 45% (10,465/23,366; mortality rate ratio 3.48, 95% CI 3.37-3.60) and at five years 69% (15,669/23,366; mortality rate ratio 2.57, 95% CI 2.50-2.63). Interpretation: Despite improved cancer treatment, venous thromboembolism in cancer patients is strongly associated with a poor prognosis. Funding: The study was supported by grants from the Independent Research Fund Denmark (record no. 3101-00102B) and the Karen Elise Jensen Foundation.