key: cord-0748906-ihoiukki authors: Hulshof, Anne‐Marije; Braeken, Dionne C. W.; Ghossein‐Doha, Chahinda; van Santen, Susanne; Sels, Jan‐Willem E. M.; Kuiper, Gerhardus J. A. J. M.; van der Horst, Iwan C. C.; ten Cate, Hugo; van Bussel, Bas C. T.; Olie, Renske H.; Henskens, Yvonne M. C. title: Hemostasis and fibrinolysis in COVID‐19 survivors 6 months after intensive care unit discharge date: 2021-09-24 journal: Res Pract Thromb Haemost DOI: 10.1002/rth2.12579 sha: c2416b01ff9d38cfb9f735c5018e99758cb9c522 doc_id: 748906 cord_uid: ihoiukki 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. Conclusions: Six months after COVID-19 ICU discharge, no persisting hypercoagulable or hypofibrinolytic profile was detected by tPA ROTEM. Nevertheless, increased Essentials • Persistence of hemostatic abnormalities remains unclear in patients with coronavirus disease 2019. • Changes in hemostasis and fibrinolysis were analyzed at discharge and 6-month follow-up. • Viscoelastic parameters of clot formation normalized over the 6-month follow-up. • Nine (41%) patients still had elevated D-dimer and/or fibrinogen at follow-up. The coronavirus disease 2019 (COVID-19)-associated prothrombotic phenotype is characterized by elevated von Willebrand factor, D-dimer, fibrinogen, and changes in global assays such as rotational thromboelastometry (ROTEM) and thromboelastography. [1] [2] [3] [4] [5] ROTEM is a whole blood viscoelastic assay that monitors the dynamic properties of clot formation. The addition of tissue-type plasminogen activator (tPA) to standard ROTEM reagents creates a novel assay (tPA ROTEM) able to both identify clot buildup and breakdown under fibrinolytic stimulus. 6 The tPA ROTEM assay might better reflect the coagulopathy in vivo compared to routine hemostasis laboratory assays. Indeed, previous studies in patients with COVID-19 demonstrated persisting hypercoagulability and impaired fibrinolysis during intensive care unit (ICU) admission, as measured with (tPA) ROTEM. 4, 5 Abnormal hemostatic viscoelastic parameters often persist upon ICU discharge, 4 and abnormalities in D-dimer concentrations have been observed several months after COVID-19 infection. 7 The presence of a so-called chronic COVID-19 syndrome may potentially be driven by microvascular thrombosis, limiting recovery. 8, 9 Although the prothrombotic phenotype during hospital admission has been extensively described, potential long-term (micro)thrombotic morbidity following ICU discharge is currently unknown. Both routine hemostasis assays and the point-of-care tPA ROTEM quickly evaluate overall hemostasis and fibrinolysis, suitable for clinical decision making during a follow-up appointment. We aimed to evaluate the changes over 6 months in routine hemostasis laboratory parameters and tPA ROTEM after COVID-19 ICU discharge. The tPA ROTEM is a whole blood viscoelastic assay, where changes in viscoelastic properties during clot formation and fibrinolysis are measured. The tPA ROTEM assay was previously described and validated by Kuiper et al. 6 In short, simultaneous addition of tissue factor (35 pM) and tPA (125 ng/mL) to the test cup results in 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. COVID-19, fibrinolysis, follow-up studies, hemostasis, thromboelastography coagulation succeeded by fibrinolysis of the clot. The maximum duration of the assay is 2 hours. The following tPA ROTEM parameters were analyzed: clotting time (CT; in seconds), maximum clot firmness (MCF; in mm), lysis onset time (LOT; time in seconds from CT until a 15% drop in MCF), and lysis time (LT; time in seconds from CT until a 90% drop in MCF). Prolonged LOT and LT suggest a hypofibrinolytic phenotype, while shortened LOT and LT illustrate hyperfibrinolysis. If 15% and/or 90% clot breakdown were not reached, LOT and LT were capped at 2 hours (7200 seconds). During ICU admission, patients had been screened for venous thromboembolism (VTE) upon clinical suspicion. 14 Computed tomography pulmonary angiogram (CTPA) was performed to diagnose pulmonary embolism (PE) and deep vein thrombosis (DVT) was confirmed by compression ultrasonography. Patients with confirmed VTE during hospital admission were treated with anticoagulants for at least 3 months. After 3 months, specialist clinicians reviewed and (dis)continued the anticoagulant treatment based on laboratory and clinical characteristics. Patients without VTE did not receive standard thromboprophylaxis after hospital discharge, unless antithrombotic treatment was indicated by comorbidities (eg, atrial fibrillation). Mann-Whitney U test and chi-square test, respectively. P < .05 was considered statistically significant. Data are presented as median (interquartile range) for continuous data and n (rel. %) for categorical data. a n = 1 missing. 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CG-D reports research support from Bayer, Abbot, Amgen, and