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Introduction Argatroban is indicated for treatment of heparin-induced thrombocytopenia, but is also used in critical ill COVID-19 patients presenting with extensive thrombin overload. Direct drug monitoring is not available and argatroban dosing is mainly based on activated partial plasmin time (aPTT), which has limitations in hypercoagulable patients with increased FVIII [1, 2]. The aim of this study was to compare correlation of routine clotting tests (aPTT, ecarin clotting time [ECA-CT] and diluted thrombin time [dTT]) [3] to argatroban plasma levels measured by gold standard mass spectrometry (LC/MS/MS). Method From 06/2021 to 03/2022, 205 samples from 22 COVID-19 ICU patients were analyzed: aPTT and dTT on STA R Max3-Analyzer (Stago Deutschland GmbH, Germany) using the BIOPHEN DTI Kit with Argatroban-calibration (CoaChrom Diagnostica GmbH, Austria);ECA-CT was measured using ClotPro ecarin assay. LC/MS/MS was performed using an RP column, a solvent gradient and an API4000 mass spectrometer with electrospray. Correlation was analyzed using Pearson correlation coefficient r in R version 3.2.4. This study was approved by the Ethics Committee of the Technical University of Dresden, Germany (BO-EK-64022022) and registered with German Clinical Trials Register DRKS00028689. Results From 205 samples with LC/MS/MS analysis, 195 were compared to aPTT, 153 to ECA-CT and 105 to dTT. In 40 samples, dTT was not measureable due high bilirubin values. Compared to LC/MS/MS, correlation of dTT was highest (r = 0.924), followed by ECA-CT (r 0.609) and aPTT (r 0.367;p < 0.001;Fig. 1). When recommended cut-offs for argatroban plasma levels (500-1000 ng/ml according to SmPC) were applied, dTT (when measurable) and ECA-CT better identified critical values of argatroban plasma values > 1000ng/ml than aPTT (Fig. 2). Conclusion Argatroban in critical ill COVID-19 patients should be monitored using dTT. If dTT is not possible or measurements are highly time-sensitive, point-of-care ClotPro ECA-test should be preferably used instead of aPTT. (Table Presented).
ABSTRACT
Introduction Anticoagulation is indicated for the prevention or therapy of thromboembolic events, but remains highly challenging considering the high risk of bleeding events in critically ill patients.Unfractionated heparin (UFH) is widely used as preferred anticoagulation for patients on intensive care units (ICU) due to its beneficial short half time and fast elimination. For monitoring of UFH, activated partial thromboplastin time (aPTT) is mainly used, but aPTT can be misleading in both directions [1]. While high factor VIII plasma values may decrease aPTT, a reduced factor XII under extracorporal circulation may prolong aPTT that no longer correlates to anticoagulation intensity [2]. Anticoagulation monitoring using specific UFH calibrated anti-Xa levels is an established alternative to overcome aPTT limitations but is rarely available 24/7 [3, 4]. Using point-of-care (POC) viscoelastic testing (VET) [5] with a specific ratio between clotting time (CT) in intrinsic test (IN-test) compared to heparinase test (HI-test) - which includes the inactivation of heparin in the probe - might help to determine the UFH effect in critically ill patients [6]. Method From 09/2020 to 07/2022, 467 samples from 120 adult ICU patients receiving UFH therapy were prospectively collected. Samples for aPTT, anti-Xa measurement and POC VET using ClotPro (Haemonetics, Boston, Massachusetts, USA) were simultaneously collected. Measurement for aPTT (C.K. Prest) and anti-Xa (Liquid AntiXa) were performed using STA R Max 3 device (Stago Deutschland GmbH, Dusseldorf). Correlation was analyzed using Kruskal-Wallis test in SPSS version 27 and R version 3.2.4. This study was approved by the local Ethics Committee at the Technische Universitat Dresden, Germany (BOEK- 374072021) and registered with the German Clinical Trials Register DRKS00028689. Results 467 samples under UFH treatment were included in this analysis, the majority of these patients were treated for COVID-19 associated acute distress syndrome. According to our institutional guidelines, anti-Xa target levels for UFH were set at 0.3-0.5 IE/ml for standard high-risk prophylaxis and 0.5-0.7 IE/ ml for therapeutic anticoagulation therapy with values < 0.3 and > 0.7 being defined as under- or over-treatment. Table 1 presents the median aPTT and CT IN/HI ratio values for patients within these anti-Xa categories. CT IN/HI ratio correlation to anti-Xa levels was considerably better than aPTT correlation (Tab. 1). Notably, aPTT could not exactly discriminate between patients receiving UFH dosages correlating to high-risk prophylaxis or therapeutic anticoagulation. Conclusion Whole blood POC VET using a specific heparinase-approach (IN/ HI ratio) is superior to aPTT in detecting patients in or out of targeted anti-Xa levels. POC VET should be made available for ICUs as bedside test and might help to guide anticoagulation management in critical ill patients, being faster and potentially more widely available than lab-based anti-Xa testing (Fig. 1). (Table Presented).
ABSTRACT
Background: COVID-19-Convalescent Plasma (CCP) showed beneficial effects when given early in the treatment course or when it contains high-titre of neutralizing antibodies. Here we present a long-term follow up of patients of the multicentric national randomized CAPSID trial that investigated the effect of CCP in hospitalized COVID-19 patients. CCP donors were also included in the follow up and severed as a control group of patients with mild to moderate disease. Method(s): Patients and donors were invited to participate in the long-term follow up. Data on long-term overall survival (OS) were available for n=52 patients (control group: n=22, high titre CCP: n=16, low-titre CCP: n=14) and n=113 donors. Structured interview and a quality of life (QoL) assessment by questionnaires (FACIT fatigue, FACIT dyspnea and EQ-ED- 5DL) were performed. Visits took place online or on site. Laboratory tests included neutralizing antibody testing by PRNT and inflammation markers. Data are given as median with IQR. Medical events were assessed and graded according to CTCAE. For donors the median follow up time was 517 (483-553) days after the first plasmapheresis and for patients 395 (371-417) days after randomization. Result(s): Medical events during follow up were reported in 27% of donors and 16% of patients (p=0.164) with grade 3 or higher in 9% of donors and 22% of patients. More patients than donors reported a decrease in their socioeconomic status and reported more frequently about GI, pulmonal, pain symptoms or alopecia (p<0.02), but no difference in neurologic symptoms including anosmia was observed. Post COVID-Scale was worse in patients with a trend for better outcome in the CCP group (p=0.089). The trend for better OS in the CCP group became more pronounced during the long-term follow up (p=0.08) and OS remained significantly better in the high dose CCP group (p=0.01). All QoL scores showed a consistent trend towards better outcomes of the CCP group. Conclusion(s): To our knowledge, this is the first long-term follow up from a randomized trial of CCP. CCP-donors with mild to moderate COVID- 19 had a significant smaller long-term disease burden than patients with severe disease. The addition of CCP added to standard treatment in severe COVID-19 showed a trend to better OS and QoL. We had previously reported significant better outcomes in the high-titre CCP subgroup (until day 60). This was even more pronounced during the long-term follow up (> 1 year).
ABSTRACT
Background: Several observational studies suggested efficacy of COVID-19 convalescent plasma (CCP) but the results of several randomized clinical trials of CCP are not consistent. The trials differ in treatment schedules in terms of timing, volume and antibody content of CCP as well as enrolled patient populations and endpoints. The CAPSID was designed at the beginning of the pandemic and assessed the efficacy of neutralizing antibody containing high-dose COVID-19 convalescent plasma (CCP) in hospitalized patients with severe COVID-19. Methods: Patients (n=105) in 13 hospitals in Germany were randomized to either receive standard treatment and three units of CCP on days 1, 3 and 5 (total dose 846 ml) (n=53) or standard treatment alone (n=52). Patients in the control group with progress on day 14 could receive CCP (crossover group;n=7) on days 15, 17 and 19. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria of severe COVID-19 on day 21. For Cross over patients a propensity matching with patients of the plasma group was performed. Results: Neutralizing antibodies were present at baseline in 18.2% of CCP and 19.2% of control group patients. In the ITT analysis the primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The CCP group showed a trend for shorter times to clinical improvement (40 days, p=0.27) and discharge from hospital (20 days, p=0.24). Among those in the CCP group who received a higher or lower cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% and 32.1% of patients The high titer group showed significantly shorter intervals to clinical improvement or hospital discharge and a better overall survival (p=0.02). None of the patients in the crossover group (CG) achieved clinical improvement and survived. Comparing the CG to 14 CCP patients matched by baseline characteristics resulted in worse OS in the CG group (p=0.02) while comparison with 6 day 14 matched patients showed equal OS. Interpretation: CCP added to standard treatment did not result in a significant difference in the primary and secondary outcomes. A pre-defined subgroup analysis showed a signal of benefit for CCP among those who received a larger amount of neutralizing antibodies. A progress on day 14 is an indicator for poor outcome in COVID-19. Late administration of CCP is not supported by our results.
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Introduction: Recent studies linked coronavirus disease 2019 (COVID-19) to thromboembolic complications likely mediated by increased blood coagulability and inflammatory endothelial impairment. Objective: We aimed to assess the risk of acute stroke in patients with COVID-19 related to clinical severity of the disease. Methods: We conducted an observational multicenter cohort study in four participating hospitals in Saxony, Germany to characterize consecutive patients with laboratory-confirmed COVID-19 who experienced acute stroke during hospitalization. Furthermore, we performed a systematic review using PubMed/MEDLINE, EMBASE, Cochrane Library and bibliographies of identified articles following PRISMA guidelines including data from observational studies of acute stroke in COVID-19 patients. Data was extracted by two independent reviewers and pooled with multicenter data to calculate risk ratios (RR) and 95% confidence intervals (95%CIs) for acute stroke related to COVID- 19 severity using random effects model. Between-study heterogeneity was assessed using Cochran's Q and I -statistics. PROSPERO identifier: CRD42020187194. Results: Of 165 patients hospitalized for COVID-19 (49.1% males, median age 67 [57-79], 72.1% severe or critical) included in the multicenter study, overall stroke rate was 4.2% (95%CI: 1.9-8.7). Systematic literature search identified two observational studies involving 576 patients that were StrokeJournal of the American Heart Association (JAHA)eligible for meta-analysis. Among 741 pooled COVID-19 patients overall stroke rate was 2.9%(95%CI: 1.9-4.5). Risk of acute stroke was increased for patients with severe compared to non-severe COVID-19 (RR 4.12, 95%CI 1.7-10.25;p=0.002) with no evidence of heterogeneity (I=0%,p=0.82). Conclusions: Synthesized analysis of data from our multicenter study and previously publishedcohorts demonstrate that severity of COVID-19 is associated with an increased risk of acute stroke, underscoring the necessity of neurological monitoring in patients infected with SARS-CoV-2.
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BACKGROUND AND PURPOSE: Recent observations linked coronavirus disease 2019 (COVID-19) to thromboembolic complications possibly mediated by increased blood coagulability and inflammatory endothelial impairment. We aimed to define the risk of acute stroke in patients with severe and non-severe COVID-19. METHODS: We performed an observational, multicenter cohort study in four participating hospitals in Saxony, Germany to characterize consecutive patients with laboratory-confirmed COVID-19 who experienced acute stroke during hospitalization. Furthermore, we conducted a systematic review using PubMed/MEDLINE, Embase, Cochrane Library and bibliographies of identified papers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines including data from observational studies of acute stroke in COVID-19 patients. Data were extracted by two independent reviewers and pooled with multicenter data to calculate risk ratios (RRs) and 95% confidence intervals (95% CIs) for acute stroke related to COVID-19 severity using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I2 statistics. International Prospective Register of Systematic Reviews registration number: CRD42020187194. RESULTS: Of 165 patients hospitalized for COVID-19 (49.1% males, median age = 67 years [57-79 years], 72.1% severe or critical) included in the multicenter study, overall stroke rate was 4.2% (95% CI: 1.9-8.7). Systematic literature search identified two observational studies involving 576 patients that were eligible for meta-analysis. Amongst 741 pooled COVID-19 patients, overall stroke rate was 2.9% (95% CI: 1.9-4.5). Risk of acute stroke was increased for patients with severe compared to non-severe COVID-19 (RR = 4.18, 95% CI: 1.7-10.25; P = 0.002) with no evidence of heterogeneity (I2 = 0%, P = 0.82). CONCLUSIONS: Synthesized analysis of data from our multicenter study and previously published cohorts indicates that severity of COVID-19 is associated with an increased risk of acute stroke.