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Background: During hospitalization for Covid-19 the prevalence of pulmonary embolism (PE) is ~15%. Occult PE may be undiagnosed during hospitalization. Also, after discharge, factors such as residual (local) inflammation and relative physical inactivity may predispose to PE. Aim(s): To study the presence of occult PE and pulmonary perfusion defects three months after discharge from hospitalization for Covid-19. Method(s): In this prospective study we performed CT pulmonary angiography (CTPA) in adults three months after discharge from hospitalization for moderate-to-critical Covid-19. Exclusion criteria: therapeutic anticoagulation, diagnosed PE during hospitalization, CTPA contra-indications. Primary outcome measure was presence of PE. Secondary outcomes were wedge shaped perfusion defects on subtraction iodine maps, D-dimer concentration, presence of Years criteria at follow-up, and pulmonary parenchymal abnormalities. Result(s): 26 patients (65% male, 61 (SD10) y, hospital length of stay 11 (IQR9-15) days, 34% ICU treatment) underwent CTPA at 13 (SD2) weeks after discharge. 25 patients (96%) had no evidence for PE while one post-ICU patient demonstrated a suspected partial occlusion of a subsegmental pulmonary artery. No wedge shaped perfusion defects were found. D-Dimer values were <1000 ng/ml in all patients and none had Years criteria. Extent of parenchymal abnormalities decreased compared to acute phase (CT severity score 7 (SD5) vs 13 (SD5), p=0.004). Conclusion(s): Prevalence of occult PE three months after discharge from hospitalization for Covid-19 was negligible in our sample. CTPA should not be routinely performed in these patients. .
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INTRODUCTION: Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. MATERIALS AND METHODS: A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. RESULTS AND CONCLUSIONS: The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.
Subject(s)
COVID-19 , Endothelin-1 , Cohort Studies , Humans , Inflammation , Pandemics , SARS-CoV-2ABSTRACT
Background : Critically ill patients with COVID-19 are at high risk of thromboembolic events, despite thromboprophylaxis with lowmolecular weight heparins (LWMH), while increased-intensity thromboprophylaxis in this patient population is associated with bleeding. This raises the question whether pharmacokinetic (PK) effects of LMWHs are predictable in these patients. Aims : To investigate whether a dosing algorithm for dalteparin administration could be designed based on clinical parameters, using PK modeling with anti-Xa levels as readout. Methods : In this explorative, observational study, we prospectively included 15 adult COVID-19 patients admitted to the intensive care unit receiving dalteparin in prophylactic-intensity (5000 IU dalteparin once daily (OD) for those <100 kg, 5000 IU dalteparin bidaily (BD) for those ≥100 kg) and therapeutic-intensity (100 IU/kg BD). A minimum of 4 anti-Xa samples per day were collected on regular timepoints over 1-3 days. PK analysis of dalteparin was performed by nonlinear mixed-effect modeling (NONMEM v7.4). The final model was used to perform Monte Carlo simulations to predict anti-Xa levels with different dalteparin regimens. The study was approved by the local medical ethics committee. Results : The data were well-fitted to a linear one compartment model. Wide interindividual variation in the parameters absorption (78%) and clearance (34%) of dalteparin was observed, not explained by clinical covariates such as creatinine clearance for elimination rate. Simulations show that prophylactic dosing in individuals <100 kg result in anti-Xa levels within generally used prophylactic targets, while increased-prophylactic dosing in those ≥100 kg result in supraprophylactic levels in 40% of patients. With therapeuticintensity dosing in secondary thromboprophylaxis, 22% of patients would be subtherapeutically, and 19% patients supratherapeutically dosed. Conclusions : Anti-Xa levels during dalteparin treatment in the critically ill COVID-19 patient are difficult to predict and often off-target. Until data from randomized clinical trials conclude on the best dosing, this suggests that anti-Xa measurements are needed to guide high-intensity dosing in the individual patient.
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Background : Patients with COVID-19 have a hypercoagulable state with increased risk of thrombotic venous events (VTE). These thrombotic complications could be responsible for a significant part of the morbidity and mortality seen in COVID-19 patients. The high incidence of VTE is seen even despite the use of apparently adequate thrombosis prophylaxis. Therefore, it is suggested that in COVID-19 patients increased intensity thromboprophylaxis or therapeutic anticoagulation should be considered. Aims : We investigated whether the use of therapeutic anticoagulation prior to infection has a beneficial effect on morbidity and mortality in hospitalized COVID-19 patients. Methods : In this multicenter retrospective cohort study, all ≥18 years old COVID-19 patients admitted to 6 hospitals in the Netherlands between March and May 2020 were included. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. Relevant secondary outcomes included admission to the intensive care unit (ICU), need for invasive mechanical ventilation, pulmonary embolism and length of hospital stay Results : A total of 1154 patients were included, of whom 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no association between prior use of therapeutic anticoagulation and in hospital mortality compared to no prior use of anticoagulation (RR 1.02 (95% CI;0.80-1.30). We also found no significant differences in secondary outcomes apart from a lower risk of pulmonary embolism in patients using therapeutic anticoagulation prior to infection (RR 0.19 (95% CI;0.05-0.80). Conclusions : Although prior therapeutic anticoagulation use is associated with reduced PE occurrence, it is not associated with better outcome parameters in hospitalized COVID-19 patients in terms of all-cause mortality, ICU admittance, need for mechanical ventilation, and length of hospital stay.
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INTRODUCTION: In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. METHODS: We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. RESULTS: In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8-15%), 16% (13-19%) and 21% (17-25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41-0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65-1.2). CONCLUSIONS: Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted.