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Background: COVID-19 patients frequently experience pulmonary embolism (PE), but its long-term consequences remain uncertain. Objectives: To assess the impact of PE in COVID-19 patients on health outcomes at 3 months after hospitalization. Methods: In this multicenter cross-sectional study, we aggregated data from existing databases to evaluate the impact of PE on health outcomes at 3 months after hospitalization. We assessed 1) questionnaires on health-related quality of life (5-level EuroQol 5-dimensional questionnaire [EQ-5D-5L] questionnaire), anxiety, depression, cognitive failure, and posttraumatic stress disorder; 2) pulmonary function tests (diffusing capacity of the lungs for carbon monoxide [DLCO] and spirometry); and 3) radiological abnormalities. We developed 3 models to assess the association between PE and the EQ-5D-5L index and the percentage of predicted DLCO (DLCO%): a crude model (model 1), adjusted for age, sex, and presence of comorbidities (model 2), and model 2 additionally adjusted for intensive care unit admission (model 3). Results: We included 465 patients who had been hospitalized for COVID-19, of whom 102 (21.9%) had developed a PE during admission. Patients with PE had poorer EQ-5D-5L index values, more impairment in pulmonary functions, and more frequent radiological abnormalities than patients without PE. Symptoms of anxiety, depression, cognitive failure, and posttraumatic stress disorder did not differ between the 2 groups. In model 2, PE was associated with lower EQ-5D-5L index and lower DLCO%. After additionally adjusting for intensive care unit admission, the association between PE and lower EQ-5D-5L index (mean difference = −0.069, [95% CI, −0.12 to −0.017]) remained but not between PE and DLCO%. Conclusion: Our findings suggest that PE in COVID-19 patients is associated with reduced health-related quality of life at 3 months after hospitalization. While PE may be a marker of COVID-19 severity, its presence during hospitalization could indicate potential long-term health issues, which may be considered during follow-up care.

Abstract The incidence of venous thrombosis, mostly pulmonary embolism (PE), ranging from local immunothrombosis to central emboli, but also deep vein thrombosis (DVT) in people with coronavirus disease 2019 (COVID‐19) is reported to be remarkably high. The relevance of better understanding, predicting, treating, and preventing COVID‐19–associated venous thrombosis meets broad support, as can be concluded from the high number of research, review, and guideline papers that have been published on this topic. The Dutch COVID & Thrombosis Coalition (DCTC) is a multidisciplinary team involving a large number of Dutch experts in the broad area of venous thrombosis and hemostasis research, combined with experts on virology, critically ill patients, pulmonary diseases, and community medicine, across all university hospitals and many community hospitals in the Netherlands. Within the consortium, clinical data of at least 5000 admitted COVID‐19–infected individuals are available, including substantial collections of biobanked materials in an estimated 3000 people. In addition to considerable experience in preclinical and clinical thrombosis research, the consortium embeds virology‐hemostasis research models within unique biosafety facilities to address fundamental questions on the interaction of virus with epithelial and vascular cells, in relation to the coagulation and inflammatory system. The DCTC has initiated a comprehensive research program to answer many of the current questions on the pathophysiology and best anticoagulant treatment of COVID‐19–associated thrombotic complications. The research program was funded by grants of the Netherlands Thrombosis Foundation and the Netherlands Organization for Health Research and Development. Here, we summarize the design and main aims of the research program.

Abstract Background In patients with a venous outflow obstruction following iliofemoral deep vein thrombosis stenting of the venous tract to prevent or alleviate postthrombotic syndrome is applied with increasing frequency. The impact of the quality of anticoagulant therapy with vitamin K antagonists (VKAs) on the development of in‐stent thrombosis is currently unknown. Objectives To determine the association between the quality of postinterventional VKA treatment and the occurrence of in‐stent thrombosis. Methods Seventy‐nine patients with iliofemoral and/or caval venous stent placement for obstruction of the venous outflow were included in this study. All patients received postinterventional VKA. The quality of VKA anticoagulant therapy was expressed as the time within therapeutic range (TTR) calculated using the linear interpolation method and as the proportion of International Normalized Ratio (INR) values

Abstract Background In the initial absence of specific reversal agents for factor Xa inhibitors (FXa‐Is), prothrombin complex concentrate (PCC) as a hemostatic agent has been recommended by guidelines. Since 2017, idarucizumab has been registered for dabigatran reversal. Still, data on the clinical outcome of direct oral anticoagulant (DOAC)‐related emergencies (major bleeding or urgent interventions) is scarce. In addition, it is unknown to what extent PCC restores thrombin generation in FXa‐I–related emergencies. Our aim was to describe management and clinical outcomes of DOAC‐related emergencies and to assess the laboratory effect of PCC in patients with FXa‐I emergencies. Methods In this prospective cohort study in 5 Dutch hospitals, patients presenting with DOAC‐related emergencies were eligible. The primary outcome was effective hemostasis according to the ISTH definition. Safety outcomes were 30‐day mortality and thromboembolic rate. In patients treated with PCC, additional blood samples were taken to assess the effect on thrombin generation. Results We included 101 patients with major bleeding (FXa‐I, 76; dabigatran, 25) and 21 patients requiring an urgent intervention (FXa‐I, 16; dabigatran, 5). Of patients with major bleeding, 67% were treated with PCC or idarucizumab. Effective hemostasis, 30‐day mortality, and thromboembolism rate were 67%, 22%, and 1%, respectively. In a subset of bleeding patients on FXa‐I managed with PCC, thrombin generation increased, with 96% immediately after PCC administration. In patients requiring an urgent intervention, effective hemostasis, 30‐day mortality, and thromboembolic rate were 95%, 14%, and 5%. Conclusions Effective hemostasis was achieved in the majority of patients presenting with DOAC‐related emergencies;, thromboembolic complications were rare, and mortality was quite high.

Abstract The goat model of atrial fibrillation (AF) allows investigation of the effect of AF on coagulation. However, assays for goat plasma are not available from commercial sources. Calibrated automated thrombography (CAT) provides a global view of the coagulation profile by assessing in vitro thrombin generation (TG). We describe the customization of the CAT assay in goat platelet‐poor plasma (PPP) and in factor Xa (FXa)‐inhibitor‐anticoagulated PPP. TG was initiated in the presence of phospholipids and either (a) PPP reagent, reagent low, or reagent high; (b) goat brain protein extraction (GBP); or (c) Russell's viper venom‐factor X activator (RVV‐X). Contact activation was assessed by adding corn trypsin inhibitor. Different concentrations of prothrombin complex concentrate (PCC) were used to determine the sensitivity of both the GBP and RVV‐X method. To obtain FXa‐inhibitor anticoagulated plasma, rivaroxaban was added to plasma. TG settings with human reagents were not suitable for goat plasma. TG triggered with GBP increased peak height and ETP values. Similarly, the RVV‐X method produced comparable TG curves and was more sensitive to PCC titration. Finally, both methods were able to detect the decrease in clotting potential induced by FXa inhibition. This is the first study that reports the customization of the CAT assay for goats. The GBP and RVV‐X methods were comparable in triggering TG in goat plasma. The RVV‐X method seemed to better discriminate changes in TG curves due to increases in clotting potential as well as to FXa inhibition by rivaroxaban in goat plasma.

Abstract Background Vaccination is the leading approach in combatting the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic. ChAdOx1 nCoV‐19 vaccination (ChAdOx1) has been linked to a higher frequency of rare thrombosis and thromboembolism. This study aimed to explore markers related to the blood coagulation system activation and inflammation, before and after ChAdOx1 vaccination. Patients and Methods An observational cohort study including 40 health care workers. Whole blood samples were collected before, and either 1 or 2 days after vaccination. Activated coagulation factors in complex with their natural inhibitors were determined by custom ELISAs, including thrombin:antithrombin (T:AT), kallikrein:C1‐esterase‐inhibitor (PKa:C1Inh), factor(F)IXa:AT, FXa:AT, FXIaAT, FXIa:alpha‐1‐antitrypsin (α1AT), FXIa:C1inh, and FVIIa:AT. Plasma concentrations of interleukin (IL)‐6 and IL‐18 were quantified via ELISA. Analyses were performed using Wilcoxon signed‐rank test. Results Levels of FVIIa:AT decreased with a median (IQR) of 707 (549–1028) pg/ml versus 598 (471–996) pg/ml, p = 0.01; and levels of IL‐6 increased, 4.0 (1.9–6.8) pg/ml versus 6.9 (3.6–12.2) pg/ml, p = 0.02, after vaccination. No changes were observed in T:AT, PKa:C1Inh, FIXa:AT, FXa:AT, FXIaAT, FXIa:α1AT, FXIa:C1inh, and IL‐18. Conclusion ChAdOx1 leads to an inflammatory response with increased levels of IL‐6. We did not observe activation of the blood coagulation system 1–2 days following vaccination.

Abstract Background The prothrombotic phenotype has been extensively described in patients with acute coronavirus disease 2019 (COVID‐19). However, potential long‐term hemostatic abnormalities are unknown. Objective To evaluate the changes in routine hemostasis laboratory parameters and tissue‐type plasminogen activator (tPA) rotational thromboelastometry (ROTEM) 6 months after COVID‐19 intensive care unit (ICU) discharge in patients with and without venous thromboembolism (VTE) during admission. Methods Patients with COVID‐19 of the Maastricht Intensive Care COVID cohort with tPA ROTEM measurement at ICU and 6‐month follow‐up were included. TPA ROTEM is a whole blood viscoelastic assay that illustrates both clot development and fibrinolysis due to simultaneous addition of tissue factor and tPA. Analyzed ROTEM parameters include clotting time, maximum clot firmness (MCF), lysis onset time (LOT), and lysis time (LT). Results Twenty‐two patients with COVID‐19 were included and showed extensive hemostatic abnormalities before ICU discharge. TPA ROTEM MCF (75 mm [interquartile range, 68‐78]‐59 mm [49‐63]; P ≤ .001), LOT (3690 seconds [2963‐4418]‐1786 seconds [1465‐2650]; P ≤ .001), and LT (7200 seconds [6144‐7200]‐3138 seconds [2591‐4389]; P ≤ .001) normalized 6 months after ICU discharge. Of note, eight and four patients still had elevated fibrinogen and D‐dimer concentrations at follow‐up, respectively. In general, no difference in median hemostasis parameters at 6‐month follow‐up was observed between patients with (n=14) and without (n=8) VTE, although fibrinogen appeared to be lower in the VTE group (VTE–, 4.3 g/L [3.7‐4.7] vs VTE+, 3.4 g/L [3.2‐4.2]; P = .05). Conclusions Six months after COVID‐19 ICU discharge, no persisting hypercoagulable or hypofibrinolytic profile was detected by tPA ROTEM. Nevertheless, increased D‐dimer and fibrinogen concentrations persist up to 6 months in some patients, warranting further exploration of the role of hemostasis in long‐term morbidity after hospital discharge.

Abstract Background Long‐term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin. Methods Patients with PE who participated in the Hokusai‐VTE trial were contacted between June 2017 and September 2020 for a single long‐term follow‐up visit. Main outcomes were the generic and disease‐specific QoL measured by the 36‐Item Short Form Health Survey (SF‐36) and Pulmonary Embolism Quality of Life questionnaire. Results We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient‐ and thrombus‐specific characteristics were similar in both groups. Mean time since randomization in the Hokusai‐VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. −1.6 to 3.2) for the SF‐36 summary mental score and 1.6 (95% CI, −0.9 to 4.1) for summary physical score. Conclusion Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long‐term QoL. Since our study was a follow‐up study from a well‐controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time.