Low-Molecular-Weight Heparin Resistance and Its Viscoelastic Assessment in Critically Ill COVID-19 Patients.

Critically ill COVID-19 patients present an inflammatory and procoagulant status with a high rate of relevant macro- and microvascular thrombosis. Furthermore, high rates of heparin resistance have been described; yet, individualized anticoagulation by drug monitoring has not been sufficiently researched. We analyzed data from critically ill COVID-19 patients treated at Innsbruck Medical University Hospital with routinely adapted low-molecular-weight heparin (LMWH) doses according to anti-Xa peak levels, and regularly performed ClotPro analyses (a viscoelastic hemostatic whole blood test). A total of 509 anti-Xa peak measurements in 91 patients were categorized as below (<0.008 IU/mL/mg), within (0.008-0-012 IU/mL/mg) or above (> 0.012 IU/mL/mg) expected ranges with respect to the administered LMWH doses. Besides intergroup comparisons, correlations between anti-Xa levels and ClotPro clotting times (CTs) were performed (226 time points in 84 patients). Anti-Xa peak levels remained below the expected range in the majority of performed measurements (63.7%). Corresponding patients presented with higher C-reactive protein and D-dimer but lower antithrombin levels when compared with patients achieving or exceeding the expected range. Consequently, higher enoxaparin doses were applied in the sub-expected anti-Xa range group. Importantly, 47 (51.6%) patients switched between groups during their intensive care unit (ICU) stay. Anti-Xa levels correlated weakly with IN test CT and moderately with Russell's viper venom (RVV) test CT. Critically ill COVID-19 patients present with a high rate of LMWH resistance but with a variable LMWH response during their ICU stay. Therefore, LMWH-anti-Xa monitoring seems inevitable to achieve adequate target ranges. Furthermore, we propose the use of ClotPro's RVV test to assess the coagulation status during LMWH administration, as it correlates well with anti-Xa levels but more holistically reflects the coagulation cascade than anti-Xa activity alone.

Predictive ability of viscoelastic testing using ClotPro® for short-term outcome in patients with severe Covid-19 ARDS with or without ECMO therapy: a retrospective study.

BACKGROUND: SARS-CoV-2 infections are suspected to trigger the coagulation system through various pathways leading to a high incidence of thromboembolic complications, hypercoagulation and impaired fibrinolytic capacity were previously identified as potentially mechanisms. A reliable diagnostic tool for detecting both is still under discussion. This retrospective study is aimed to examine the prognostic relevance of early viscoelastic testing compared to conventional laboratory tests in COVID-19 patients with acute respiratory distress syndrome (ARDS). METHODS: All mechanically ventilated patients with COVID-19 related ARDS treated in our intensive care unit (ICU) between January and March 2021 were included in this study. Viscoelastic testing (VET) was performed using the ClotPro® system after admission to our ICU. Prevalence of thromboembolic events was observed by standardized screening for venous and pulmonary thromboembolism using complete compression ultrasound and thoracic computed tomography pulmonary angiography at ICU admission, respectively. We examined associations between the severity of ARDS at admission to our ICU, in-hospital mortality and the incidence of thromboembolic events comparing conventional laboratory analysis and VET. ECMO related coagulopathy was investigated in a subgroup analysis. The data were analyzed using the Mann-Whitney U test. RESULTS: Of 55 patients enrolled in this study, 22 patients required treatment with ECMO. Thromboembolic complications occurred in 51% of all patients. Overall hospital mortality was 55%. In patients with thromboembolic complications, signs of reduced fibrinolytic capacity could be detected in the TPA assay with prolonged lysis time, median 460 s (IQR 350-560) vs 359 s (IQR 287-521, p = 0.073). Patients with moderate to severe ARDS at admission to our ICU showed increased maximum clot firmness as a sign of hypercoagulation in the EX-test (70 vs 67 mm, p < 0.05), FIB-test (35 vs 24 mm, p < 0.05) and TPA-test (52 vs 36 mm, p < 0.05) as well as higher values of inflammatory markers (CRP, PCT and IL6). ECMO patients suffered more frequently from bleeding complications (32% vs 15%). CONCLUSION: Although, the predictive value for thromboembolic complications or mortality seems limited, point-of-care viscoelastic coagulation testing might be useful in detecting hypercoagulable states and impaired fibrinolysis in critically ill COVID-19 ARDS patients and could be helpful in identifying patients with a potentially very severe course of the disease.

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review.

During sepsis, an initial prothrombotic shift takes place, in which coagulatory acute-phase proteins are increased, while anticoagulatory factors and platelet count decrease. Further on, the fibrinolytic system becomes impaired, which contributes to disease severity. At a later stage in sepsis, coagulation factors may become depleted, and sepsis patients may shift into a hypo-coagulable state with an increased bleeding risk. During the pro-coagulatory shift, critically ill patients have an increased thrombosis risk that ranges from developing micro-thromboses that impair organ function to life-threatening thromboembolic events. Here, thrombin plays a key role in coagulation as well as in inflammation. For thromboprophylaxis, low molecular weight heparins (LMWH) and unfractionated heparins (UFHs) are recommended. Nevertheless, there are conditions such as heparin resistance or heparin-induced thrombocytopenia (HIT), wherein heparin becomes ineffective or even puts the patient at an increased prothrombotic risk. In these cases, argatroban, a direct thrombin inhibitor (DTI), might be a potential alternative anticoagulatory strategy. Yet, caution is advised with regard to dosing of argatroban especially in sepsis. Therefore, the starting dose of argatroban is recommended to be low and should be titrated to the targeted anticoagulation level and be closely monitored in the further course of treatment. The authors of this review recommend using DTIs such as argatroban as an alternative anticoagulant in critically ill patients suffering from sepsis or COVID-19 with suspected or confirmed HIT, HIT-like conditions, impaired fibrinolysis, in patients on extracorporeal circuits and patients with heparin resistance, when closely monitored.

Changes in characteristics and outcomes of critically ill COVID-19 patients in Tyrol (Austria) over 1 year.

BACKGROUND: Widely varying mortality rates of critically ill Coronavirus disease 19 (COVID-19) patients in the world highlighted the need for local surveillance of baseline characteristics, treatment strategies and outcome. We compared two periods of the COVID-19 pandemic to identify important differences in characteristics and therapeutic measures and their influence on the outcome of critically ill COVID-19 patients. METHODS: This multicenter prospective register study included all patients with a SARS-CoV­2 infection confirmed by polymerase chain reaction, who were treated in 1 of the 12 intensive care units (ICU) from 8 hospitals in Tyrol, Austria during 2 defined periods (1 February 2020 until 17 July: first wave and 18 July 2020 until 22 February 2021: second wave) of the COVID-19 pandemic. RESULTS: Overall, 508 patients were analyzed. The majority (n = 401) presented during the second wave, where the median age was significantly higher (64 years, IQR 54-74 years vs. 72 years, IQR 62-78 years, p < 0.001). Invasive mechanical ventilation was less frequent during the second period (50.5% vs 67.3%, p = 0.003), as was the use of vasopressors (50.3% vs. 69.2%, p = 0.001) and renal replacement therapy (12.0% vs. 19.6%, p = 0.061), which resulted in shorter ICU length of stay (10 days, IQR 5-18 days vs. 18 days, IQR 5-31 days, p < 0.001). Nonetheless, ICU mortality did not change (28.9% vs. 21.5%, p = 0.159) and hospital mortality even increased (22.4% vs. 33.4%, p = 0.039) in the second period. Age, frailty and the number of comorbidities were significant predictors of hospital mortality in a multivariate logistic regression analysis of the overall cohort. CONCLUSION: Advanced treatment strategies and learning effects over time resulted in reduced rates of mechanical ventilation and vasopressor use in the second wave associated with shorter ICU length of stay. Despite these improvements, age appears to be a dominant factor for hospital mortality in critically ill COVID-19 patients.

Viscoelastic Hemostatic Assays: A Primer on Legacy and New Generation Devices.

Viscoelastic hemostatic assay (VHAs) are whole blood point-of-care tests that have become an essential method for assaying hemostatic competence in liver transplantation, cardiac surgery, and most recently, trauma surgery involving hemorrhagic shock. It has taken more than three-quarters of a century of research and clinical application for this technology to become mainstream in these three clinical areas. Within the last decade, the cup and pin legacy devices, such as thromboelastography (TEG® 5000) and rotational thromboelastometry (ROTEM® delta), have been supplanted not only by cartridge systems (TEG® 6S and ROTEM® sigma), but also by more portable point-of-care bedside testing iterations of these legacy devices (e.g., Sonoclot®, Quantra®, and ClotPro®). Here, the legacy and new generation VHAs are compared on the basis of their unique hemostatic parameters that define contributions of coagulation factors, fibrinogen/fibrin, platelets, and clot lysis as related to the lifespan of a clot. In conclusion, we offer a brief discussion on the meteoric adoption of VHAs across the medical and surgical specialties to address COVID-19-associated coagulopathy.

Structured ICU resource management in a pandemic is associated with favorable outcome in critically ill COVID­19 patients.

INTRODUCTION: On February 25, 2020, the first 2 patients were tested positive for severe acute respiratory syndrome coronavirus­2 (SARS-CoV-2) in Tyrol, Austria. Rapid measures were taken to ensure adequate intensive care unit (ICU) preparedness for a surge of critically ill coronavirus disease-2019 (COVID-19) patients. METHODS: This cohort study included all COVID-19 patients admitted to an ICU with confirmed or strongly suspected COVID-19 in the State of Tyrol, Austria. Patients were recorded in the Tyrolean COVID-19 intensive care registry. Date of final follow-up was July 17, 2020. RESULTS: A total of 106 critically ill patients with COVID-19 were admitted to 1 of 13 ICUs in Tyrol from March 9 to July 17, 2020. Median age was 64 years (interquartile range, IQR 54-74 years) and the majority of patients were male (76 patients, 71.7%). Median simplified acute physiology score III (SAPS III) was 56 points (IQR 49-64 points). The median duration from appearance of first symptoms to ICU admission was 8 days (IQR 5-11 days). Invasive mechanical ventilation was required in 72 patients (67.9%) and 6 patients (5.6%) required extracorporeal membrane oxygenation treatment. Renal replacement therapy was necessary in 21 patients (19.8%). Median ICU length of stay (LOS) was 18 days (IQR 5-31 days), median hospital LOS was 27 days (IQR 13-49 days). The ICU mortality was 21.7% (23 patients), hospital mortality was 22.6%. There was no significant difference in ICU mortality in patients receiving invasive mechanical ventilation and in those not receiving it (18.1% vs. 29.4%, p = 0.284). As of July 17th, 2020, two patients are still hospitalized, one in an ICU, one on a general ward. CONCLUSION: Critically ill COVID-19 patients in Tyrol showed high severity of disease often requiring complex treatment with increased lengths of ICU and hospital stay. Nevertheless, the mortality was found to be remarkably low, which may be attributed to our adaptive surge response providing sufficient ICU resources.

Impaired fibrinolysis in critically ill COVID-19 patients.

BACKGROUND: Critically ill coronavirus disease 2019 (COVID-19) patients present with a hypercoagulable state with high rates of macrovascular and microvascular thrombosis, for which hypofibrinolysis might be an important contributing factor. METHODS: We retrospectively analysed 20 critically ill COVID-19 patients at Innsbruck Medical University Hospital whose coagulation function was tested with ClotPro® and compared with that of 60 healthy individuals at Augsburg University Clinic. ClotPro is a viscoelastic whole blood coagulation testing device. It includes the TPA test, which uses tissue factor (TF)-activated whole blood with added recombinant tissue-derived plasminogen activator (r-tPA) to induce fibrinolysis. For this purpose, the lysis time (LT) is measured as the time from when maximum clot firmness (MCF) is reached until MCF falls by 50%. We compared COVID-19 patients with prolonged LT in the TPA test and those with normal LT. RESULTS: Critically ill COVID-19 patients showed hypercoagulability in ClotPro assays. MCF was higher in the EX test (TF-activated assay), IN test (ellagic acid-activated assay), and FIB test (functional fibrinogen assay) with decreased maximum lysis (ML) in the EX test (hypofibrinolysis) and highly prolonged TPA test LT (decreased fibrinolytic response), as compared with healthy persons. COVID-19 patients with decreased fibrinolytic response showed higher fibrinogen levels, higher thrombocyte count, higher C-reactive protein levels, and decreased ML in the EX test and IN test. CONCLUSION: Critically ill COVID-19 patients have impaired fibrinolysis. This hypofibrinolytic state could be at least partially dependent on a decreased fibrinolytic response.