Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the... Show moreVirus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to 122 immune parameters in 102 hospitalised patients with moderate and severe COVID-19 in a longitudinal design. Delayed viral clearance was associated with more severe disease and was associated with higher levels of SARS-CoV-2-specific (neutralising) antibodies over time, increased numbers of neutrophils, monocytes, basophils, and a range of pro-inflammatory cyto-/chemokines illustrating ongoing, partially Th2 dominating, immune activation. In contrast, early viral clearance and less critical illness correlated with the peak of neutralising antibodies, higher levels of CD4 T cells, and in particular naive CD4+ T cells, suggesting their role in early control of SARS-CoV-2 possibly by proving appropriate B cell help. Higher counts of naive CD4+ T cells also correlated with lower levels of MIF, IL-9, and TNF-beta, suggesting an indirect role in averting prolonged virus-induced tissue damage. Collectively, our data show that naive CD4+ T cell play a critical role in rapid viral T cell control, obviating aberrant antibody and cytokine profiles and disease deterioration. These data may help in guiding risk stratification for severe COVID-19. Show less
Background: Coagulation abnormalities and coagulopathy are recognized as consequences of severe acute respiratory syndrome coronavirus 2 infection and the resulting coronavirus disease 2019 (COVID... Show moreBackground: Coagulation abnormalities and coagulopathy are recognized as consequences of severe acute respiratory syndrome coronavirus 2 infection and the resulting coronavirus disease 2019 (COVID-19). Specifically, venous thromboembolism (VTE) has been reported as a frequent complication. By May 27, 2021, at least 93 original studies and 25 meta-analyses investigating VTE incidence in patients with COVID-19 had been published, showing large heterogeneity in reported VTE incidence ranging from 0% to 85%. This large variation complicates interpretation of individual study results as well as comparisons across studies, for example, to investigate changes in incidence over time, compare subgroups, and perform meta-analyses. Objectives: This study sets out to provide an overview of sources of heterogeneity in VTE incidence studies in patients with COVID-19, illustrated using examples. Methods: The original studies of three meta-analyses were screened and a list of sources of heterogeneity that may explain observed heterogeneity across studies was composed. Results: The sources of heterogeneity in VTE incidence were classified as clinical sources and methodologic sources. Clinical sources of heterogeneity include differences between studies regarding patient characteristics that affect baseline VTE risk and protocols used for VTE testing. Methodologic sources of heterogeneity include differences in VTE inclusion types, data quality, and the methods used for data analysis. Conclusions: To appreciate reported estimates of VTE incidence in patients with COVID-19 in relation to its etiology, prevention, and treatment, researchers should unambiguously report about possible clinical and methodological sources of heterogeneity in those estimates. This article provides suggestions for that. Show less
The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic... Show moreThe risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I-2 = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I-2 = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I-2 = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE. Show less
Stoevelaar, R.; Juffermans, C.C.M.; Roorda, I.M.M.; Nijs, E.J.M. de; Hoornweg, J.; Cannegieter, S.C.; Linden, Y.M. van der 2022
Objective: This study aimed to examine whether the 10-item Risk Score List (RSL) accurately predicts delirium in patients admitted to inpatient hospice care and whether this instrument can be... Show moreObjective: This study aimed to examine whether the 10-item Risk Score List (RSL) accurately predicts delirium in patients admitted to inpatient hospice care and whether this instrument can be simplified. Determining the risk for developing delirium can help to treat these patients in a timely manner. Methods: This was a retrospective medical record study in patients who died in 2019 or 2020 in three hospices. Predictive values were examined using Cox regression analysis, crosstabs, and C-statistic. Results: In total, 240 patients were included. Median age at admission was 78 (IQR 70-84) years. Primary diagnosis most often was cancer (n = 186, 78%); 173 (72%) patients had an increased risk of delirium according to RSL, of whom 120 (69%) developed delirium. Overall, 147 (61%) patients developed delirium. The RSL significantly predicted future delirium (HR 3.25, CI 1.87-5.65, p < 0.01) and had a sensitivity of 85%, a specificity of 43%, positive predictive value of 62%, negative predictive value of 73%, and a C-statistic of 0.64. Simplifying the RSL to four items still significantly predicted future delirium, with similar predictive values. Conclusion: Delirium occurs in more than half of patients admitted to hospice care. The RSL can be simplified to four items, without compromising on predictive accuracy. Show less
Background Colorectal cancer patients have an increased risk of developing venous thromboembolism (VTE), resulting in increased morbidity and mortality. Because the exact mechanism is yet unknown,... Show moreBackground Colorectal cancer patients have an increased risk of developing venous thromboembolism (VTE), resulting in increased morbidity and mortality. Because the exact mechanism is yet unknown, risk prediction is still challenging; therefore, new biomarkers are needed. MicroRNAs (miRNAs) are small, relatively stable RNAs, that regulate a variety of cellular processes, and are easily measured in body fluids. Objective The aim of this study was to identify novel tumor-expressed miRNAs associated with VTE. Methods In a cohort of 418 colorectal cancer patients diagnosed between 2001 and 2015 at the Leiden University Medical Center, 23 patients (5.5%) developed VTE 1 year before or after cancer diagnosis. Based on availability of frozen tumor material, tumor cells of 17 patients with VTE and 18 patients without VTE were isolated using laser capture microdissection and subsequently analyzed on the Illumina sequencing platform NovaSeq600 using 150-bp paired-end sequencing. Cases and controls were matched on age, sex, tumor stage, and grade. Differential miRNA expression was analyzed using edgeR. Results A total of 547 miRNAs were detected. Applying a 1.5-fold difference and false discovery rate of <0.1, 19 tumor-miRNAs were differentially regulated in VTE cases versus controls, with hsa-miR-3652, hsa-miR-92b-5p, and hsa-miR-10,394-5p as most significantly downregulated. Seven of the 19 identified miRNAs were predicted to regulate the gonadotropin-releasing hormone receptor pathway. Conclusion We identified 19 differentially regulated tumor-expressed miRNAs in colorectal cancer-associated VTE, which may provide insights into the biological mechanism and in the future might have potential to serve as novel, predictive biomarkers. Show less
Background Glioblastoma patients are considered to be at high risk of venous thromboembolism (VTE) and major bleeding (MB), although reliable incidence estimates are lacking. Moreover, the risk of... Show moreBackground Glioblastoma patients are considered to be at high risk of venous thromboembolism (VTE) and major bleeding (MB), although reliable incidence estimates are lacking. Moreover, the risk of arterial thromboembolism (ATE) in these patients is largely unknown. Our aim was to assess the cumulative incidence, predictors, and prognostic impact of VTE, ATE, and MB on subsequent complications and mortality. Methods Cohort study of 967 consecutive patients diagnosed with glioblastoma between 2004-2020 in two hospitals. Patients were followed from 6 months before date of histopathological glioblastoma diagnosis up to 2 years after, or until an outcome of interest (VTE, ATE, and MB) or death occurred, depending on the analysis. Cumulative incidences were estimated with death as competing risk. Cox regression was used to identify predictors and the prognostic impact. Results A total of 101 patients were diagnosed with VTE, 50 with ATE, and 126 with MB during a median follow-up of 15 months (interquartile range 9.0-22). The adjusted 1-year cumulative incidence of VTE was 7.5% (95% confidence interval [CI] 5.9-9.3), of ATE 4.1% (95% CI 3.0-5.6), and of MB 12% (95% CI 9.6-14). Older age, type of surgery, and performance status were predictors of VTE. Incident VTE during follow-up was associated with MB (adjusted HR 4.7, 95% CI 2.5-9.0). MB and VTE were associated with mortality (adjusted HR 1.7, 95% CI 1.3-2.1 and 1.3, 95% CI 1.0-1.7, respectively). Conclusion We found considerable incidences of VTE and MB in glioblastoma patients, with both complications associated with poorer prognosis. Our observations emphasize the need for prospective studies to determine optimal thromboprophylaxis and VTE treatment strategy in these patients. 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: Whether certain activities can trigger spontaneous intracerebral hemorrhage (ICH) remains unknown. Insights into factors that trigger vessel rupture resulting in ICH improves knowledge... Show moreBackground: Whether certain activities can trigger spontaneous intracerebral hemorrhage (ICH) remains unknown. Insights into factors that trigger vessel rupture resulting in ICH improves knowledge on the pathophysiology of ICH. We assessed potential trigger factors and their risk for ICH onset. Methods: We included consecutive patients diagnosed with ICH between July 1, 2013, and December 31, 2019. We interviewed patients on their exposure to 12 potential trigger factors (eg, Valsalva maneuvers) in the (hazard) period soon before onset of ICH and their normal exposure to these trigger factors in the year before the ICH. We used the case-crossover design to calculate relative risks (RR) for potential trigger factors. Results: We interviewed 149 patients (mean age 64, 66% male) with ICH. Sixty-seven (45%) had a lobar hemorrhage, 60 (40%) had a deep hemorrhage, 19 (13%) had a cerebellar hemorrhage, and 3 (2%) had an intraventricular hemorrhage. For ICH in general, there was an increased risk within an hour after caffeine consumption (RR=2.5 [95% CI=1.8-3.6]), within an hour after coffee consumption alone (RR=4.8 [95% CI=3.3-6.9]), within an hour after lifting >25 kg (RR=6.6 [95% CI=2.2-19.9]), within an hour after minor head trauma (RR=10.1 [95% CI=1.7-60.2]), within an hour after sexual activity (RR=30.4 [95% CI=16.8-55.0]), within an hour after straining for defecation (RR=37.6 [95% CI=22.4-63.4]), and within an hour after vigorous exercise (RR=21.8 [95% CI=12.6-37.8]). Within 24 hours after flu-like disease or fever, the risk for ICH was also increased (RR=50.7 [95% CI=27.1-95.1]). Within an hour after Valsalva maneuvers, the RR for deep ICH was 3.5 (95% CI=1.7-6.9) and for lobar ICH the RR was 2.0 (95% CI=0.9-4.2). Conclusions: We identified one infection and several blood pressure related trigger factors for ICH onset, providing new insights into the pathophysiology of vessel rupture resulting in ICH. Show less
Background: Lower-leg injury and knee arthroscopy are both associated with venous thromboembolism (VTE). The mechanism of VTE in both situations is unknown, including the role of procoagulant... Show moreBackground: Lower-leg injury and knee arthroscopy are both associated with venous thromboembolism (VTE). The mechanism of VTE in both situations is unknown, including the role of procoagulant microparticles. This may provide useful information for individualizing thromboprophylactic treatment in both patient groups. Objective: We aimed to study the effect of (1) lower-leg trauma and (2) knee arthroscopy on procoagulant phospholipid-dependent (PPL) activity plasma levels. Methods: POT-(K)CAST trial participants who did not develop VTE were randomly selected for the current study. Plasma was collected shortly after lower-leg trauma or before and after knee arthroscopy. For aim 1, samples of 67 patients with lower-leg injury were compared with control samples (preoperative samples of 74 patients undergoing arthroscopy). Linear regression was used to obtain mean ratios (natural logarithm retransformed data), adjusted for age, sex, body mass index, infections, and comorbidities. For aim 2, pre- and postoperative samples of 49 patients undergoing arthroscopy were compared using paired t tests. PPL activity was measured using modified activated factor X-dependent PPL clotting assay. Results: For aim 1, PPL activity levels were almost threefold higher in patients with lower-leg injury compared with controls, that is, mean ratio, 2.82 (95% confidence interval [CI], 1.98-4.03). For aim 2, postoperative PPL activity levels did not change significantly, that is, mean change, -0.72 mU/mL (95% Cl, -2.03 to 0.59). Conclusion: Lower-leg trauma was associated with increased plasma levels of PPL activity, in contrast to knee arthroscopy. Lower-leg trauma triggers the release of procoagulant microparticles. Show less
Men seem to have a higher intrinsic risk of venous thromboembolism (VTE) than women, regardless of age. To date, this difference has not been explained. By integrating state-of-the-art research... Show moreMen seem to have a higher intrinsic risk of venous thromboembolism (VTE) than women, regardless of age. To date, this difference has not been explained. By integrating state-of-the-art research presented at the International Society on Thrombosis and Haemostasis Congress of 2021 with the available literature, we address potential explanations for this intriguing risk difference between men and women. We discuss the role of exogenous and endogenous sex hormones as the most important known sex-specific determinants of VTE risk. In addition, we highlight clues on the role of sex hormones and VTE risk from clinical scenarios such as pregnancy and the polycystic ovary syndrome. Furthermore, we address new potential sex-specific risk factors and unanswered research questions, which could provide more insight in the intrinsic risk difference between men and women, such as body height and differences in body fat distribution, leading to dysregulation of metabolism and inflammation. Show less
Lith, T.J. van; Sluis, W.M.; Wijers, N.T.; Meijer, F.J.A.; Kamphuis-van Ulzen, K.; Bresser, J. de; ... ; Leeuw, F.E. de 2022
Background: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of... Show moreBackground: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of silent cerebral ischemia, and the long-term functional outcome in these patients are currently unknown. Patients and methods: CORONavirus and Ischemic Stroke (CORONIS) is a multicentre prospective cohort study investigating the prevalence, risk factors and long-term incidence of (silent) cerebral ischemia, and the long-term functional outcome among patients with COVID-19. We aim to include 200 adult patients hospitalized with COVID-19 without symptomatic ischemic stroke to investigate the prevalence of silent cerebral ischemia compared with 60 (matched) controls with MRI. In addition, we will identify potential risk factors and/or causes of cerebral ischemia in COVID-19 patients with (n = 70) or without symptomatic stroke (n = 200) by means of blood sampling, cardiac workup and brain MRI. We will measure functional outcome and cognitive function after 3 and 12 months with standardized questionnaires in all patients with COVID-19. Finally, the long-term incidence of (new) silent cerebral ischemia in patients with COVID-19 will be assessed with follow up MRI (n = 120). The CORONIS study is designed to add further insight into the prevalence, long-term incidence and risk factors of cerebral ischemia, and the long-term functional outcome in hospitalized adult patients with COVID-19. Show less
Background: Surgery is a well-known risk factor for venous thromboembolism (VTE). However, for several minor surgical procedures, thromboprophylaxis is not advised.Objectives: These "low-risk"... Show moreBackground: Surgery is a well-known risk factor for venous thromboembolism (VTE). However, for several minor surgical procedures, thromboprophylaxis is not advised.Objectives: These "low-risk" procedures include a wide variation of interventions for which we estimated the VTE risk to verify their "low-risk" status.Patients/Methods: We used data from a large population-based case-control study (Multiple Environment and Genetic Assessment study) into causes of VTE, and linked these to the Dutch Hospital Data Registry to identify exposure to surgical procedures. Logistic regression was used to calculate odds ratios for the 90-day and 1-year relative risks of VTE following these procedures, which were adjusted for body mass index (BMI), sex, age, comorbidities, and infection/inflammation.Results: We included 4247 patients with VTE and 5538 control subjects. Median age and BMI were 48.5 years and 25.5 m2/kg, respectively. Nine unique procedures or groups of procedures were analyzed. One hundred twenty-three participants-90 cases and 33 controls-had undergone a minor procedure within 90 days of the index date, resulting in a 3.5-fold (OR, 3.5; 95% CI, 2.3-5.3) overall increased VTE risk. Further-more, venous stripping (OR, 7.2; 95% CI, 2.4-21.2), open abdominal/inguinal hernia repair (OR, 3.7; 95% CI, 1.2-11.6), and laparoscopic cholecystectomy (OR, 3.2; 95% CI, 1.0-10.6) were associated with an increased risk. Other minor procedures were less strongly or not associated with an increased risk. In the 1-year period before the index date, all odds ratios were lower.Conclusion: Of the "low-risk" procedures, we found that venous stripping, open abdominal/inguinal hernia repair, and laparoscopic cholecystectomy were associated with a clearly increased risk of VTE within 90 postoperative days. Show less
Background In January 2021, the Dutch vaccination program against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was started. Clinical studies have shown that systemic reactions occur... Show moreBackground In January 2021, the Dutch vaccination program against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was started. Clinical studies have shown that systemic reactions occur in up to 50% of vaccine recipients. Therefore, COVID-19 vaccination could affect anticoagulation control, potentially leading to an increased risk of thrombotic events and bleeding complications.Aims This article investigates whether the BNT162b2 vaccine affects anticoagulation control in outpatients using vitamin K antagonists (VKAs).Methods A case-crossover study was performed in a cohort of outpatient VKA users from four Dutch anticoagulation clinics who received a BNT162b2 vaccine. International normalized ratio (INR) results and VKA dosages before the first vaccination, the reference period, were compared with those after the first and second vaccination.Results A total of 3,148 outpatient VKA users were included, with amean age (standard deviation) of 86.7 (8.7) years, of whom 43.8% weremale, 67.0% used acenocoumarol, and 33.0% phenprocoumon. We observed a decrease of 8.9% of INRs within range in the standard intensity group (target INR 2.0-3.0). There was both an increased risk of supratherapeutic (odds ratio [OR] = 1.34 [95% confidence interval [CI] 1.08-1.67]) and subtherapeutic levels (OR = 1.40 [95% CI 1.08-1.83]) after first vaccination. In the high-intensity group (target INR 2.5-3.5), the risk of a supratherapeutic INR was 2.3 times higher after first vaccination (OR = 2.29 [95% CI 1.22-4.28]) and 3.3 times higher after second vaccination (OR = 3.25 [95% CI 1.06-9.97]).Conclusion BNT162b2 was associated with an immediate negative effect on anticoagulation control in patients treated with VKAs, so it is advisable to monitor the INR shortly after vaccination, even in stable patients.[GRAPHICS]. Show less
Piers, S.R.; Androulakis, A.F.; Yim, K.S.; Rein, N. van; Venlet, J.; Kapel, G.F.; ... ; Zeppenfeld, K. 2022
Background: Spontaneous nonsustained ventricular tachycardia (NSVT) on Holter, VT inducibility during electrophysiology study, and late gadolinium enhancement (LGE) on cardiac magnetic resonance ... Show moreBackground: Spontaneous nonsustained ventricular tachycardia (NSVT) on Holter, VT inducibility during electrophysiology study, and late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) have been associated with sustained ventricular arrhythmias (SVAs) in nonischemic dilated cardiomyopathy (DCM). This study aimed to analyze whether these parameters carry independent prognostic value for spontaneous SVA in DCM. Methods: Between 2011 and 2018, patients with the DCM clinical spectrum and documented SVA, suspected SVA, or considered to be at intermediate or high risk for SVA were enrolled in the prospective Leiden Nonischemic Cardiomyopathy Study. Patients underwent a comprehensive evaluation including 24-hour Holter, LGE-CMR, and electrophysiology study. Holters were assessed for the presence of NSVT (>= 3 beats; rate, >= 120 bpm; lasting <30 s) and NSVT characteristics (coupling interval, duration, cycle length, morphology, regularity). Patients were followed at 6 to 12 monthly intervals. Results: Of all 115 patients (age, 59 +/- 12 years; 77% men; left ventricular ejection fraction, 33 +/- 13%; history of SVA, 36%; LGE in 63%; median LGE mass, 13 g; interquartile range, 8-23 g), 62 (54%) had NSVT on Holter, and sustained monomorphic VT was inducible in 34 of 114 patients (30%). NSVT was not associated with LGE on CMR or VT inducibility during electrophysiology study nor were its features (all P>0.05). During 4.0 +/- 1.8 years of follow-up, SVA occurred in 39 patients (34%). NSVT (HR, 4.47 [95% CI, 1.87-10.72]; P=0.001) and VT inducibility (HR, 3.08 [95% CI, 1.08-8.81]; P=0.036) were independently associated with SVA during follow-up. A bivariable model including only noninvasively acquired parameters also allowed identification of a high-risk subgroup (ie, those with both NSVT and LGE on CMR). The findings remained similar when only patients without prior SVA were included. Conclusions: In patients with DCM, NSVT on Holter and VT inducibility during electrophysiology study predict SVA during follow-up independent of LGE on CMR. NSVTs may serve as an initiator, and sustained VT inducibility indicates the presence of the substrate for SVA in DCM. Show less
Background Venous thromboembolism (VTE) is a frequent cardiovascular disease with severe complications, including recurrence and death. There is a great need for alternative prophylactic treatment... Show moreBackground Venous thromboembolism (VTE) is a frequent cardiovascular disease with severe complications, including recurrence and death. There is a great need for alternative prophylactic treatment options as anticoagulation is accompanied by increased bleeding risk. Statins are reported to reduce the risk of incident and recurrent VTE, but the mechanisms are elusive. Procoagulant phospholipids (PPL), and phosphatidylserine in particular, are crucial for efficient coagulation activation, but no studies have investigated the effect of statin treatment on plasma PPL activity. Objectives To investigate the impact of rosuvastatin treatment on plasma PPL activity and levels of extracellular vesicles (EVs). Patients/Methods Patients with a history of VTE (>= 18 years) allowed to stop anticoagulant treatment were randomized to either 20 mg/day of rosuvastatin treatment or no treatment for 28 days in the Statins Reduce Thrombophilia (NCT01613794) trial. Plasma samples were collected at baseline and study end. PPL activity was measured in samples from 245 participants using a factor Xa-dependent clotting assay and EV levels by flow cytometry. Results Rosuvastatin treatment yielded an overall 22% (95% confidence interval [CI] -38.2 to -5.8) reduction in PPL activity, and 37% (95% CI -62.9 to -11.2) reduction in PPL activity in participants with a history of pulmonary embolism. The effect of rosuvastatin on plasma PPL activity was not explained by changes in total cholesterol nor change in levels of total- or platelet-derived EVs. Conclusions Rosuvastatin treatment caused a substantial decrease in plasma PPL activity, suggesting that a PPL-dependent attenuation of coagulation activation may contribute to a reduced VTE risk following statin treatment. Show less
Introduction Patients with lower-leg cast immobilization and patients undergoing knee arthroscopy have an increased risk of venous thrombosis (VT). Guidelines are ambiguous about thromboprophylaxis... Show moreIntroduction Patients with lower-leg cast immobilization and patients undergoing knee arthroscopy have an increased risk of venous thrombosis (VT). Guidelines are ambiguous about thromboprophylaxis use, and individual risk factors for developing VT are often ignored. To assist in VT risk stratification and guide thromboprophylaxis use, various prediction models have been developed. These models depend largely on clinical factors and provide reasonably good C-statistics of around 70%. We explored using protein levels in blood plasma measured by multiplexed quantitative targeted proteomics to predict VT. Our aim was to assess whether a VT risk prediction model based on absolute plasma protein quantification is possible. Methods We used internal standards to quantify proteins in less than 10 mu l plasma. We measured 270 proteins in samples from patients scheduled for knee arthroscopy or with lower-leg cast immobilization. The two prospective POT-(K)CAST trails allow complementary views of VT signature in blood, namely pre and post trauma, respectively. From approximately 3000 patients, 31 patients developed VT who were included and matched with double the number of controls. Results Top discriminating proteins between cases and controls included APOC3, APOC4, APOC2, ATRN, F13B, and F2 in knee arthroscopy patients and APOE, SERPINF2, B2M, F13B, AFM, and C1QC in patients with lower-leg cast. A logistic regression model with cross-validation resulted in C-statistics of 88.1% (95% CI: 85.7-90.6%) and 79.6% (95% CI: 77.2-82.0%) for knee arthroscopy and cast immobilization groups respectively. Conclusions Promising C-statistics merit further exploration of the value of proteomic tests for predicting VT risk upon additional validation. Show less
Background Non-valvular atrial fibrillation (NVAF) patients are advised to switch from a vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) when time in therapeutic range (TTR) is low.... Show moreBackground Non-valvular atrial fibrillation (NVAF) patients are advised to switch from a vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) when time in therapeutic range (TTR) is low. Objective To examine if pre-switch TTR determines persistence patterns in NVAF patients who are switched from a VKA to DOAC. Patients/Methods Adult NVAF patients from three Dutch anticoagulation clinics who were newly switched from a VKA to DOAC between July 1, 2013 and September 30, 2018 were stratified by pre-switch TTR levels. DOAC prescription records were examined to determine persistence patterns according to a 100-day prescription gap. Cumulative incidences of non-persistence to DOAC were estimated using the cumulative incidence competing risk method. The association of pre-switch TTR levels with DOAC non-persistence was evaluated by Cox regression models. Results A total of 3696 NVAF patients were included, of whom 690 (18.7%) had a pre-switch TTR <= 45%. After switching from VKA to DOAC, 14.0% (95% confidence interval [CI] 11.3-17.0%) of the patients with a pre-switch TTR <= 45% became non-persistent to DOAC within 1 year, while 9.8% (95% CI 8.7-11.0%) did in those with a pre-switch TTR > 45%. In a multivariable model, a pre-switch TTR <= 45% was associated with a higher risk of non-persistence to DOAC (adjusted hazard ratio 1.55, 95% CI 1.22-1.97). Results were similar when using other cut-off points (60% or 70%) to define a low TTR. Conclusion NVAF patients switching from VKA to DOAC due to a low pre-switch TTR saw a worse persistence pattern to DOAC after the switch compared to patients with a high pre-switch TTR. Show less
Background Non-valvular atrial fibrillation (NVAF) patients are advised to switch from a vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) when time in therapeutic range (TTR) is low.... Show moreBackground Non-valvular atrial fibrillation (NVAF) patients are advised to switch from a vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) when time in therapeutic range (TTR) is low. Objective To examine if pre-switch TTR determines persistence patterns in NVAF patients who are switched from a VKA to DOAC. Patients/Methods Adult NVAF patients from three Dutch anticoagulation clinics who were newly switched from a VKA to DOAC between July 1, 2013 and September 30, 2018 were stratified by pre-switch TTR levels. DOAC prescription records were examined to determine persistence patterns according to a 100-day prescription gap. Cumulative incidences of non-persistence to DOAC were estimated using the cumulative incidence competing risk method. The association of pre-switch TTR levels with DOAC non-persistence was evaluated by Cox regression models. Results A total of 3696 NVAF patients were included, of whom 690 (18.7%) had a pre-switch TTR <= 45%. After switching from VKA to DOAC, 14.0% (95% confidence interval [CI] 11.3-17.0%) of the patients with a pre-switch TTR <= 45% became non-persistent to DOAC within 1 year, while 9.8% (95% CI 8.7-11.0%) did in those with a pre-switch TTR > 45%. In a multivariable model, a pre-switch TTR <= 45% was associated with a higher risk of non-persistence to DOAC (adjusted hazard ratio 1.55, 95% CI 1.22-1.97). Results were similar when using other cut-off points (60% or 70%) to define a low TTR. Conclusion NVAF patients switching from VKA to DOAC due to a low pre-switch TTR saw a worse persistence pattern to DOAC after the switch compared to patients with a high pre-switch TTR. Show less
Toorop, M.M.A.; Rein, N. van; Nierman, M.C.; Vermaas, H.W.; Huisman, M.V.; Meer, F.J.M. van der; ... ; Lijfering, W.M. 2021
Background Direct oral anticoagulants (DOACs) do not require concentration monitoring. However, whether DOAC concentrations are stable and their variation between and within patients is not well... Show moreBackground Direct oral anticoagulants (DOACs) do not require concentration monitoring. However, whether DOAC concentrations are stable and their variation between and within patients is not well studied. Methods Patients on vitamin K antagonists (VKA) who switched to rivaroxaban, apixaban, or dabigatran were included between 2018 and 2020. Blood was drawn at DOAC trough and peak concentrations at week 0, 2, and 8. Plasma drug concentrations were determined by anti-factor Xa concentrations (rivaroxaban, apixaban) or diluted thrombin time (dabigatran). Inter- and intra-individual variability was assessed by calculating the coefficient of variation (CV). Linear regression models were employed to evaluate associations between DOAC trough concentrations and previous VKA dosage, creatinine clearance, and body mass index (BMI). Results One hundred fifty-two patients were included, of whom 96 (63%) were male and with a mean age of 73.9 +/- 8.4 years. For the inter-individual variability, the CV ranged between 48% and 81% for trough values and between 25% and 69% for peak values among patients using the recommended DOAC dose. Intra-individual variability was substantially lower, as here the CV ranged between 18% and 33% for trough values and between 15% and 29% for peak values among patients using the recommended DOAC dose. Previous VKA dosage and creatinine clearance were inversely associated with DOAC trough concentrations. No association was found between BMI and DOAC trough concentrations. Conclusion Inter-individual variability of DOAC concentrations was higher than intra-individual variability. Lower previous VKA dosage and creatinine clearance were associated with higher DOAC trough concentrations. These findings support further study into an optimal target range, in which the risks of both bleeding and thrombosis are minimal. Show less
Aims Persistence with direct oral anticoagulants (DOACs) has become a concern in non-valvular atrial fibrillation (NVAF) patients, but whether this affects prognosis is rarely studied. We... Show moreAims Persistence with direct oral anticoagulants (DOACs) has become a concern in non-valvular atrial fibrillation (NVAF) patients, but whether this affects prognosis is rarely studied. We investigated the persistence with oral anticoagulants (OACs) and its association with prognosis among a nationwide cohort of NVAF patients.Methods and results DOAC-naive NVAF patients who started to use DOACs for ischaemic stroke prevention between 2013 and 2018 were included using Dutch national statistics. Persistence with OACs was determined based on the presence of a 100-day gap between the last prescription and the end of study period. In 93 048 patients, 75.7% had a baseline CHA(2)DS(2)-VASc score of >= 2. The cumulative incidence of persistence with OACs was 88.1% [95% confidence interval (CI) 87.9-88.3%], 82.6% (95% CI 82.3-82.9%), 77.7% (95% CI 77.3-78.1%), and 72.0% (95% CI 71.5-72.5%) at 1, 2, 3, and 4 years after receiving DOACs, respectively. Baseline characteristics associated with better persistence with OACs included female sex, age range 65-74 years, permanent atrial fibrillation, previous exposure to vitamin K antagonists, stroke history (including transient ischaemic attack), and a CHA(2)DS(2)-VASc score >= 2. Non-persistence with OACs was associated with an increased risk of the composite outcome of ischaemic stroke and ischaemic stroke-related death [adjusted hazard ratio (aHR) 1.79, 95% CI 1.49-2.15] and ischaemic stroke (aHR 1.58, 95% CI 1.29-1.93) compared with being persistent with OACs.Conclusion At least a quarter of NVAF patients were non-persistent with OACs within 4 years, which was associated with poor efficacy of ischaemic stroke prevention. The identified baseline characteristics may help identify patients at risk of non-persistence. Show less
