Novel biomarkers are needed to improve current imperfect risk prediction models for cancer-associated thrombosis (CAT). We recently identified an RNA-sequencing profile that associates with CAT in... Show moreNovel biomarkers are needed to improve current imperfect risk prediction models for cancer-associated thrombosis (CAT). We recently identified an RNA-sequencing profile that associates with CAT in colorectal cancer (CRC) patients, with REG4, SPINK4, and SERPINA1 as the top-3 upregulated genes at mRNA level. In the current study, we investigated whether protein expression of REG4, SPINK4 and alpha-1 antitrypsin (A1AT, encoded by SERPINA1) in the tumor associated with CAT in an independent cohort of CRC patients. From 418 patients with resected CRC, 18 patients who developed CAT were age, sex, and tumor stage-matched to 18 CRC patients without CAT. Protein expression was detected by immunohistochemical staining and scored blindly by assessing the H-score (percentage positive cells*scoring intensity). The association with CAT was assessed by means of logistic regression, using patients with an H-score below 33 as reference group. The odds ratios (ORs) for developing CAT for patients with A1AThigh, REG4high, SPINK4high tumors were 3.5 (95%CI 0.8–14.5), 2.0 (95%CI 0.5–7.6) and 2.0 (95%CI 0.5–7.4) when compared to A1ATlow, REG4low, SPINK4low, respectively. The OR was increased to 24.0 (95%CI 1.1–505.1) when two proteins were combined (A1AThigh/REG4high). This nested case–control study shows that combined protein expression of A1AT and REG4 associate with CAT in patients with colorectal cancer. Therefore, REG4/A1AT are potential biomarkers to improve the identification of patients with CRC who may benefit from thromboprophylaxis. Show less
This thesis addresses the pathophysiology of stress related diseases, taking two rare diseases, in which the hypothalamic-pituitary-adrenal axis and cortisol play a key role, as a model for stress... Show moreThis thesis addresses the pathophysiology of stress related diseases, taking two rare diseases, in which the hypothalamic-pituitary-adrenal axis and cortisol play a key role, as a model for stress vulnerability of the brain and the eye. The second aim of this thesis is to describe the organization of thromboprophylaxis management, and the outcome evaluation and quality of care for patients treated for Cushing’s syndrome. For more informatie, please refer tot he summary in the pdf of the thesis. Show less
Haalen, F.M. van; Kaya, M.; Pelsma, I.C.M.; Dekkers, O.M.; Biermasz, N.R.; Cannegieter, S.C.; ... ; Endo-ERN Cushing Thrombosis study 2022
Background Cushing's syndrome (CS) is associated with an hypercoagulable state and an increased risk of venous thromboembolism (VTE). Evidence-based guidelines on thromboprophylaxis strategies in... Show moreBackground Cushing's syndrome (CS) is associated with an hypercoagulable state and an increased risk of venous thromboembolism (VTE). Evidence-based guidelines on thromboprophylaxis strategies in patients with CS are currently lacking. We aimed to map the current clinical practice for thromboprophylaxis management in patients with CS across reference centers (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN), which are endorsed specifically for the diagnosis and treatment of CS. Using the EU survey tool, a primary screening survey, and subsequently a secondary, more in-depth survey were developed. Results The majority of the RCs provided thromboprophylaxis to patients with CS (n = 23/25), although only one center had a standardized thromboprophylaxis protocol (n = 1/23). RCs most frequently started thromboprophylaxis from CS diagnosis onwards (n = 11/23), and the majority stopped thromboprophylaxis based on individual patient characteristics, rather than standardized treatment duration (n = 15/23). Factors influencing the initiation of thromboprophylaxis were 'medical history of VTE' (n = 15/23) and 'severity of hypercortisolism' (n = 15/23). Low-Molecular-Weight-Heparin was selected as the first-choice anticoagulant drug for thromboprophylaxis by all RCs (n = 23/23). Postoperatively, the majority of RCs reported 'severe immobilization' as an indication to start thromboprophylaxis in patients with CS (n = 15/25). Most RCs (n = 19/25) did not provide standardized testing for variables of hemostasis in the postoperative care of CS. Furthermore, the majority of the RCs provided preoperative medical treatment to patients with CS (n = 23/25). About half of these RCs (n = 12/23) took a previous VTE into account when starting preoperative medical treatment, and about two-thirds (n = 15/23) included 'reduction of VTE risk' as a goal of treatment. Conclusions There is a large practice variation regarding thromboprophylaxis management and perioperative medical treatment in patients with CS, even in Endo-ERN RCs. Randomized controlled trials are needed to establish the optimal prophylactic anticoagulant regimen, carefully balancing the increased risk of (perioperative) bleeding, and the presence of additional risk factors for thrombosis. Show less
Background: Patients with hip fractures (HF) have an increased risk of venous thromboembolism (VTE). In elective orthopedic surgery direct oral anticoagulants (DOACs) have proven to be similarly or... Show moreBackground: Patients with hip fractures (HF) have an increased risk of venous thromboembolism (VTE). In elective orthopedic surgery direct oral anticoagulants (DOACs) have proven to be similarly or more effective compared to low molecular weight heparin (LMWH), but DOACs are not yet approved for thromboprophylaxis in trauma patients with HF. The aim of this study was to systematically review the literature comparing the effectiveness of DOACs and LMWH for thromboprophylaxis in trauma patients with surgically treated HF.Materials and Methods: We searched PubMed, the Cochrane Library, Web of Science, and Embase. The primary outcome was the incidence of VTE (symptomatic and asymptomatic combined). Secondary outcomes were symptomatic VTE; a symptomatic VTE, symptomatic deep venous thrombosis (DVT); symptomatic pulmonary embolism (PE); major, clinically relevant non-major (CRNM), and minor bleeding. Meta-analysis was performed to compare the odds of VTE and secondary outcomes between DOACs and LMWH.Results: The search resulted in 738 titles. Five studies matched inclusion criteria. In total, 4748 hip fracture patients were analyzed (DOACs: 2276 patients, LMWH: 2472 patients). The pooled odds ratio for the risk of VTE for DOAC use was 0.52 (95% confidence interval 0.25-1.11, p = 0.09) compared to LMWH. No statistically significant differences between DOAC and LMWH were found for asymptomatic VTE, symptomatic DVT, PE, major or CRNM bleeding, and minor bleeding.Conclusions: Meta-analysis of the literature suggests that DOACs are associated with equivalent effectiveness and safety compared to LMWH. (C) 2021 The Authors. Published by Elsevier Ltd. Show less
Background: Trauma patients are at a significant risk of venous thromboembolism (VTE), with lower extremity fractures (LEF) being independent risk factors. Use of direct oral anticoagusants (DOACs)... Show moreBackground: Trauma patients are at a significant risk of venous thromboembolism (VTE), with lower extremity fractures (LEF) being independent risk factors. Use of direct oral anticoagusants (DOACs) for VTE prophylaxis is effective in elective orthopedic surgery, but currently not approved for trauma patients. The primary objective of this study was to compare the effectiveness and safety of thromboprophylaxis of DOACs with lowmolecular-weight heparin (LMWH) in trauma patients sustaining LEF.Materials and methods: We included adult trauma patients admitted to trauma quality improvement program participating trauma centers (between 2013 and 2016), who sustained LEF and were started on DOACs or LMWH for thromboprophylaxis after admission. Propensity score matching was performed to compare symptomatic VTE and bleeding control interventions between the groups.Results: Of 1,009,922 patients in trauma quality improvement program, 167,640 met inclusion criteria (165,009 received LMWH and 2631 received DOACs). After propensity score matching, 2280 predominantly elderly (median age: 67 y) isolated femur fracture patients (median ISS: 10) were included in each group (4560 patients in total). Symptomatic VTE occurred in 1.4% of patients in both matched groups (P = 0.992). Bleeding control interventions occurred less often in the DOAC group, albeit statistically insignificant (5.8% versus 6.0%, P = 0.772).Conclusions: This study found similar rates of VTE and bleeding control measures for thromboprophylaxis with DOACs or LMWH in matched trauma patients with LEF. Further prospective research is warranted to consolidate the safety of DOAC thromboprophylaxis in trauma patients with LEF. Favorable oral administration and likely increased adherence could benefit this high-risk population. (C) 2020 The Authors. Published by Elsevier Inc. Show less
Klok, F.A.; Kruip, M.J.H.A.; Meer, N.J.M. van der; Arbous, M.S.; Gommers, D.A.M.P.J.; Kant, K.M.; ... ; Endeman, H. 2020
Introduction: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the... Show moreIntroduction: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available.Methods: We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital.Results: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications.Conclusion: The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence. Show less
