Longitudinal soluble marker profiles reveal strong association between cytokine storms resulting from macrophage activation and disease severity in COVID-19 disease.

SARS-CoV2 infection results in a range of disease severities, but the underlying differential pathogenesis is still not completely understood. At presentation it remains difficult to estimate and predict severity, in particular, identify individuals at greatest risk of progression towards the most severe disease-states. Here we used advanced models with circulating serum analytes as variables in combination with daily assessment of disease severity using the SCODA-score, not only at single time points but also during the course of disease, to correlate analyte levels and disease severity. We identified a remarkably strong pro-inflammatory cytokine/chemokine profile with high levels for sCD163, CCL20, HGF, CHintinase3like1 and Pentraxin3 in serum which correlated with COVID-19 disease severity and overall outcome. Although precise analyte levels differed, resulting biomarker profiles were highly similar at early and late disease stages, and even during convalescence similar biomarkers were elevated and further included CXCL3, CXCL6 and Osteopontin. Taken together, strong pro-inflammatory marker profiles were identified in patients with COVID-19 disease which correlated with overall outcome and disease severity.

Multiple Joint Arthroplasty in Hip and Knee Osteoarthritis Patients: A National Longitudinal Cohort Study.

BACKGROUND: Many patients suffer from osteoarthritis (OA) in multiple joints, possibly resulting in multiple joint arthroplasties (MJAs). Primarily, we determined the cumulative incidence (Cin) of MJA in hip and knee joints up to 10 years. Secondly, we calculated the mean time between the first and subsequent joint arthroplasty, and evaluated the different MJA trajectories. Lastly, we compared patient characteristics and outcomes (functionality and pain) after surgery between MJA patients and single hip arthroplasty or knee arthroplasty (HA and KA) patients. METHODS: Primary index (first) HA or KA for OA were extracted from the Dutch Arthroplasty Register. The 1, 2, 5, and 10-year Cin (including competing risk death) of MJA, mean time intervals, and MJA-trajectories were calculated and stratified for primary index HA or KA. Sex, preoperative age, and body mass index were compared using ordinal logistic regression. Outcomes, measured preoperatively, 3, 6, and 12 months postoperatively (function: Hip Disability or Knee Injury and OA Outcome Score; Pain: Numerical Rating Scale), were compared using linear regression. RESULTS: A total of 140,406 HA-patients and 140,268 KA-patients were included. One, 2, 5, and 10-year Cin for a second arthroplasty were respectively 8.9% [95% confidence interval (CI): 8.7 to 9.0], 14.3% [95% CI: 14.1 to 14.5], 24.0% [95% CI: 23.7 to 24.2], and 32.7% [95% CI: 32.2 to 33.1] after index HA, and 9.5% [95% CI: 9.4 to 9.7], 16.0% [95% CI: 15.9 to 16.2], 26.4% [95% CI: 26.1 to 26.6], and 35.8% [95% CI: 35.4 to 36.3] after index KA. The 10-year Cin for > 2 arthroplasties were small in both the index HA and KA groups. Time-intervals from first to second, third, and fourth arthroplasty were 26 [95% CI: 26.1 to 26.7], 47 [95% CI: 46.4 to 48.4], and 58 [95% CI: 55.4 to 61.1] months after index HA, and 26 [95% CI: 25.9 to 26.3], 52 [95% CI: 50.8 to 52.7], and 61 [95% CI: 58.3 to 63.4] months after index KA. There were 83% of the second arthroplasties placed in the contralateral cognate joint (ie, knee or hip). Differences in postoperative functionality and pain between MJAs and single HAs and KAs were small. CONCLUSIONS: The 10-year Cin showed that about one-third of patients received a second arthroplasty after approximately 2 years, with the majority in the contralateral cognate joint. Few patients received > 2 arthroplasties within 10 years. Being a women, having a higher body mass index, and being younger increased the odds of MJA. Postoperative outcomes were slightly negatively affected by MJA.

Coexisting atrial fibrillation and cancer: time trends and associations with mortality in a nationwide Dutch study.

BACKGROUND AND AIMS: Coexisting atrial fibrillation (AF) and cancer challenge the management of both. The aim of the study is to comprehensively provide the epidemiology of coexisting AF and cancer. METHODS: Using Dutch nationwide statistics, individuals with incident AF (n = 320 139) or cancer (n = 472 745) were identified during the period 2015-19. Dutch inhabitants without a history of AF (n = 320 135) or cancer (n = 472 741) were matched as control cohorts by demographic characteristics. Prevalence of cancer/AF at baseline, 1-year risk of cancer/AF diagnosis, and their time trends were determined. The association of cancer/AF diagnosis with all-cause mortality among those with AF/cancer was estimated by using time-dependent Cox regression. RESULTS: The rate of prevalence of cancer in the AF cohort was 12.6% (increasing from 11.9% to 13.2%) compared with 5.6% in the controls; 1-year cancer risk was 2.5% (stable over years) compared with 1.8% in the controls [adjusted hazard ratio (aHR) 1.52, 95% confidence interval (CI) 1.46-1.58], which was similar by cancer type. The rate of prevalence of AF in the cancer cohort was 7.5% (increasing from 6.9% to 8.2%) compared with 4.3% in the controls; 1-year AF risk was 2.8% (stable over years) compared with 1.2% in the controls (aHR 2.78, 95% CI 2.69-2.87), but cancers of the oesophagus, lung, stomach, myeloma, and lymphoma were associated with higher hazards of AF than other cancer types. Both cancer diagnosed after incident AF (aHR 7.77, 95% CI 7.45-8.11) and AF diagnosed after incident cancer (aHR 2.55, 95% CI 2.47-2.63) were associated with all-cause mortality, but the strength of the association varied by cancer type. CONCLUSIONS: Atrial fibrillation and cancer were associated bidirectionally and were increasingly coexisting, but AF risk varied by cancer type. Coexisting AF and cancer were negatively associated with survival.

Genetic polymorphisms and major bleeding risk during vitamin K antagonists treatment: The BLEEDS case-cohort.

BACKGROUND: Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk. AIM: To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1). METHODS: A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression. RESULTS: Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively). CONCLUSIONS: CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.

Cardiovascular risk profile in two cohorts of young apparently healthy South Asian descendants in the Netherlands: still a long way to go!

BACKGROUND: Cardiovascular disease (CVD) imposes a major healthcare burden on young descendants of South Asian migrants living in the western world. In comparison to the native population, the prevalence is significantly higher and the prevalence of CVD risk factors is increasing rapidly. The cardiovascular risk profile and 10-year risk scores of South Asian descendants were evaluated in two cohorts with a 10-year time difference. METHODS: Two cross-sectional studies, conducted in 2004 and 2014, focused on asymptomatic South Asian descendants aged 18-59 years were performed. A short questionnaire, BMI, waist circumference, blood pressure, and nonfasting blood tests were obtained. The cohort of 2014 was matched with the cohort of 2004, based on age, gender, and family history of CVD. RESULTS: In 2014, 674 South Asians (44% men, age 38.2 ±â€…12.0 years) were matched with 674 South Asians (44% men, age 38.3 ±â€…12.1 years) included in 2004. Notably, hypertension prevalence decreased significantly in 2014 (10.6% vs 23.1% in 2004, P  < 0.001), while mean BMI increased (26.1 vs 24.9, P  < 0.001). The mean Framingham risk score was lower in 2014 (5.31 ±â€…6.19%) than in 2004 (6.45 ±â€…8.02%, P  < 0.05). CONCLUSION: This study demonstrates that South Asian descendants in 2014 have a lower but still high absolute risk for coronary events compared to 2004. Important differences in cardiovascular risk profile exist. Despite improvements, South Asian descendants in 2014 still face a high absolute risk for coronary events compared to 2004, indicating the necessity for continued primary prevention and lifestyle interventions.

Hormonal contraceptive use after a first venous thrombotic event and the risk of recurrence in premenopausal women.

BACKGROUND: Extensive evidence is available on hormonal contraceptive (HC) use and the risk of a first venous thromboembolism (VTE) event. Despite recommendations to discontinue combined HC (CHC) use, some women continue or start its use after a first VTE. OBJECTIVES: We aimed to evaluate the VTE recurrence risk associated with HC use in premenopausal women. METHODS: Premenopausal women with a first VTE included in the Multiple Environmental and Genetic Assessment of Venous Thrombosis study between 1999 and 2004 were followed for a recurrence until 2010. Data on HC use were available through linkage to the Dutch Foundation for Pharmaceutical Statistics. The risk of recurrence was assessed 1) during anticoagulant therapy and 2) after cessation of anticoagulant therapy. Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs adjusted for age and body mass index at baseline and thromboprophylaxis use during follow-up. RESULTS: Six hundred fifty women were uniquely linked and followed for a total of 3538 person-years (median, 6.1 years), during which 57 VTE recurrences occurred. Five occurred (8.8%) during anticoagulation treatment, with no clear risk difference for CHC use vs nonuse (HR, 0.8; 95% CI, 0.1-8.2). After anticoagulation cessation, CHC use was associated with a 2.4-fold higher risk of recurrence (HR, 2.4; 95% CI, 1.2-5.0) compared with nonuse. Recurrence risk for levonorgestrel-releasing intrauterine device use was similar to that for nonuse (HR, 0.9; 95% CI, 0.3-3.1). CONCLUSION: CHC use after a first VTE is safe during anticoagulant use but substantially increases the risk of a recurrent VTE event in absence of anticoagulant use. This study adds to the evidence regarding the use of a levonorgestrel-releasing intrauterine device as a safe alternative.

Tailored anticoagulant treatment after a first venous thromboembolism: protocol of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study - cohort-based randomised controlled trial.

INTRODUCTION: Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks. METHODS AND ANALYSIS: The L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences. TRIAL REGISTRATION NUMBER: NCT06087952.

The association of tumor-expressed REG4, SPINK4 and alpha-1 antitrypsin with cancer-associated thrombosis in colorectal cancer.

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 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.

Rotational thromboelastometry as a biomarker for mortality - The Maastricht Intensive Care COVID cohort.

BACKGROUND: Patients with severe coronavirus disease 2019 (COVID-19) present with persisting hypercoagulability, hypofibrinolysis and prolonged clot initiation as measured with viscoelastic assays. The objective of this study was to investigate the trajectories of traditional assays of hemostasis, routine and tissue plasminogen activator (tPA) rotational thromboelastometry (ROTEM) in COVID-19 patients and to study their association with mortality. METHODS: Patients enrolled within the Maastricht Intensive Care COVID (MaastrICCht) cohort were included. Traditional assays of hemostasis (prothrombin time; PT, fibrinogen and D-dimer) were measured daily and ROTEM EXTEM, FIBTEM and tPA assays were performed weekly. Trajectories of these biomarkers were analyzed over time for survivors and non-survivors using linear mixed-effects models. Additional Fine and Gray competing risk survival analysis was performed for the first available measurement after intubation. RESULTS: Of the 138 included patients, 57 (41 %) died in the intensive care unit (ICU). Over 450, 400 and 1900 individual measurements were available for analysis of routine, tPA ROTEM and traditional assays of hemostasis, respectively, with a median [IQR] follow-up of 15 [8-24] days. Non-survivors on average had prolonged CT (clotting time) and increased fibrinogen compared to survivors. MCF (maximum clot firmness), LOT (lysis onset time), LT (lysis time) and PT measurements increased more over time in non-survivors compared to survivors. Associations persisted after adjustment for demographics and disease severity. EXTEM and FIBTEM CT at intubation were associated with increased 45-day ICU mortality. CONCLUSIONS: ROTEM measurements demonstrate a further increase of hypercoagulability and (hypo)fibrinolysis parameters in non-survivors throughout ICU admission. Furthermore, prolonged CT at intubation was associated with higher 45-day ICU mortality.

Coagulation profiles during and after anabolic androgenic steroid use: data from the HAARLEM study.

Background: Anabolic androgenic steroids (AAS) are thought to increase venous thromboembolism (VTE) risk. Objectives: We investigated whether AAS influence coagulation parameters associated with VTE by assessing their changes during and after AAS use. Methods: The HAARLEM study enrolled 100 male amateur athletes voluntarily starting an AAS cycle between 2015 and 2018. We measured procoagulant and anticoagulant protein levels, D-dimer levels, endogenous thrombin potential (ETP), and clot lysis time (CLT) at baseline and during 2 years of follow-up. Changes in coagulation during AAS cycle, 3 months after its discontinuation, and 1 year after its inclusion compared with baseline were estimated using linear mixed models. The associations between AAS dose and duration of use with these outcomes were studied through adjusted multivariable linear regression. Results: Participants used AAS for a median of 13 weeks (IQR: 10-23) with a median weekly dose of 901 mg (IQR: 634-1345 mg). Mean levels of multiple coagulation factors (F) increased during use compared with baseline, whereas FVIII and von Willebrand factor levels remained unchanged. Protein S and D-dimer showed the biggest increase (22% [95% CI: 15-29] and 1.3-fold [95% CI: 1.2-1.5], respectively). CLT was 8 minutes longer (95% CI: 5-10) and ETP was 165 nM∗min (95% CI: -205 to -124) lower during the AAS cycle. A high weekly AAS dose and short cycle duration were associated with changes in protein S and ETP during use. All parameters returned to baseline values 3 months after discontinuation and remained similar after. Conclusion: During AAS use, procoagulant and anticoagulant protein levels increased in a reversible manner. The overall balance did not suggest a clear procoagulant state.

Coagulation factors II, V, VII, IX, X and XI and mortality - a cohort study.

Background: Elevated levels of coagulation factors (F) II (FII), FV, FVII, FIX, FX, and FXI have often been related with coronary heart disease, ischemic stroke, and venous thrombosis (VT). However, there are few studies on their associations with all-cause mortality. Objective: We explored whether elevated levels of FII, FV, FVII, FIX, FX, and FXI are associated with an increased risk of death in patients who had VT and in individuals from the general population. Methods: We followed 1919 patients with previous VT and 2800 age- and sex-matched community controls in whom coagulation factor levels were measured. A high coagulation factor was defined as the >90th percentile of normal in the controls. Cox regression analyses were adjusted for age and sex and for being a patient with VT or being a control subject. Results: The median age at time of enrolment was 48 years for both patients and controls, and slightly more women than men were followed. Over a median follow-up of 6.1 years for patients and 5.0 years for controls, there were 79 and 60 deaths in patient and controls respectively. There was no association of FII, FV, FVII, FIX, FX, and FXI with all-cause mortality in patients or in control individuals. Conclusions: Elevated levels of FII, FV, FVII, FIX, FX, and FXI levels may not be associated with an increased risk of all-cause mortality. Only for cardiac death, an association with high FX and FXI was found, which confirms the findings of previous studies, but numbers were small.

Daily disease severity in patients with COVID-19 admitted to the hospital: The SCODA (severity of coronavirus disease assessment) score.

BACKGROUND: A multitude of diagnostic and predictive algorithms have been designed for COVID-19. However, currently no score can accurately quantify and track day-to-day disease severity in hospitalised patients with COVID-19. We aimed to design such a score to improve pathophysiological insight in COVID-19. METHODS: Development of the Severity of COronavirus Disease Assessment (SCODA) score was based on the 4C Mortality score but patient demographic variables that remain constant during admission were excluded. Instead, parameters associated with breathing and oxygenation were added to reflect the daily condition. The SCODA score was subsequently applied to the BEAT-COVID cohort to describe COVID-19 severity over time and to determine the timing of clinical recovery for each patient, an important marker in pathophysiological studies. The BEAT-COVID study included patients with PCR confirmed COVID-19 who were hospitalized between April 2020 and March 2021 in the Leiden University Medical Center, The Netherlands. RESULTS: The SCODA score consists of 6 clinical and 2 routine lab parameters. 191 patients participated in the BEAT-COVID study. Median age was 66, and 74.4% was male. The modal timepoint at which recovery was clinically initiated occurred on days 8 and 24 since symptom onset for non-ICU and ICU-patients, respectively. CONCLUSIONS: We developed a daily score which can be used to track disease severity of patients admitted due to COVID-19. This score is useful for improving insight in COVID-19 pathophysiology, its clinical course and to evaluate interventions. In a future stage this score can also be used in other (emerging) infectious respiratory diseases.

Thromboembolic and bleeding complications during interruptions and after discontinuation of anticoagulant treatment in patients with atrial fibrillation and active cancer: A daily practice evaluation.

BACKGROUND AND AIMS: Cancer provides challenges to the continuity of anticoagulant treatment in patients with atrial fibrillation (AF), e.g. through cancer-related surgery or complications. We aimed to provide data on the incidence and reasons for interrupting and discontinuing anticoagulant treatment in AF patients with cancer and to assess its contribution to the risk of thromboembolism (TE) and major bleeding (MB). METHODS: This retrospective study identified AF patients with cancer in two hospitals between 2012 and 2017. Data on anticoagulant treatment, TE and MB were collected during two-year follow-up. Incidence rates (IR) per 100 patient-years and adjusted hazard ratios (aHR) were obtained for TE and MB occurring during on- and off-anticoagulant treatment, during interruption and after resumption, and after permanent discontinuation. RESULTS: 1213 AF patients with cancer were identified, of which 140 patients permanently discontinued anticoagulants and 426 patients experienced one or more interruptions. Anticoagulation was most often interrupted or discontinued due to cancer-related treatment (n = 441, 62 %), bleeding (n = 129, 18 %) or end of life (n = 36, 5 %). The risk of TE was highest off-anticoagulation and during interruptions, with IRs of 19 (14-25)) and 105 (64-13), and aHRs of 3.1 (1.9-5.0) and 4.6 (2.4-9.0), respectively. Major bleeding risk were not only increased during an interruption, but also in the first 30 days after resumption, with IRs of 33 (12-72) and 30 (17-48), and aHRs of 3.3 (1.1-9.8) and 2.4 (1.2-4.6), respectively. CONCLUSIONS: Interruption of anticoagulation therapy harbors high TE and MB risk in AF patients with cancer. The high incidence rates call for better (periprocedural) anticoagulant management strategies tailored to the cancer setting.

Changes in incidence of hospitalization for cardiovascular diseases during the COVID-19 pandemic in The Netherlands in 2020.

This population-based cohort study aimed to describe changes in incidence of cardiovascular disease (CVD) hospital diagnoses during the COVID-19 pandemic in The Netherlands compared with the pre-pandemic period. We used Dutch nationwide statistics about hospitalizations to estimate incidence rate ratios (IRR) of hospital diagnoses of CVD during the first and second COVID-19 waves in The Netherlands in 2020 versus the same periods in 2019. Compared with 2019, the incidence rate of a hospital diagnosis of ischemic stroke (IRR 0.87; 95% CI 0.79-0.95), major bleeding (IRR 0.74; 95% CI 0.68-0.82), atrial fibrillation (IRR 0.73; 95% CI 0.65-0.82), myocardial infarction (IRR 0.78; 95% CI 0.72-0.84), and heart failure (IRR 0.74; 95% CI 0.65-0.85) declined during the first wave, but returned to pre-pandemic levels throughout 2020. However, the incidence rate of a hospital diagnosis of pulmonary embolism (PE) increased during both the first and second wave in 2020 compared with 2019 (IRR 1.30; 95% CI 1.15-1.48 and IRR 1.31; 95% CI 1.19-1.44, respectively). In conclusion, we observed substantial declines in incidences of CVD during the COVID-19 pandemic in The Netherlands in 2020, especially during the first wave, with an exception for an increase in incidence of PE. This study contributes to quantifying the collateral damage of the COVID-19 pandemic.