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.

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.

ECMO Predictors of Mortality: A 10-Year Referral Centre Experience.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a specialised life support modality for patients with refractory cardiac or respiratory failure. Multiple studies strived to evaluate the benefits of ECMO support, but its efficacy remains controversial with still inconsistent and sparse information. METHODS: This retrospective analysis included patients with ECMO support, admitted between January 2010 and December 2019 at a tertiary university ECMO referral centre in Austria. The primary endpoint of the study was overall all-cause three-month mortality with risk factors and predictors of mortality. Secondary endpoints covered the analysis of demographic and clinical characteristics of patients needing ECMO, including incidence and type of adverse events during support. RESULTS: In total, 358 patients fulfilled inclusion criteria and received ECMO support due to cardiogenic shock (258, 72%), respiratory failure (88, 25%) or hypothermia (12, 3%). In total, 41% (145) of patients died within the first three months, with the median time to death of 9 (1-87) days. The multivariate analysis identified hypothermia (HR 3.8, p < 0.001), the Simplified Acute Physiology Score III (HR 1.0, p < 0.001), ECMO initiation on weekends (HR 1.6, p = 0.016) and haemorrhage during ECMO support (HR 1.7, p = 0.001) as factors with higher risk for mortality. Finally, the most frequent adverse event was haemorrhage (160, 45%) followed by thrombosis. CONCLUSIONS: ECMO is an invasive advanced support system with a high risk of complications. Nevertheless, well-selected patients can be successfully rescued from life-threatening conditions by prolonging the therapeutic window to either solve the underlying problem or install a long-term assist device. Hypothermia, disease severity, initiation on weekends and haemorrhage during ECMO support increase the risk for mortality. In the case of decision making in a setting of limited (ICU) resources, the reported risk factors for mortality may be contemplable, especially when judging a possible ECMO support termination.

Diagnostic Modalities in Critical Care: Point-of-Care Approach.

The concept of intensive care units (ICU) has existed for almost 70 years, with outstanding development progress in the last decades. Multidisciplinary care of critically ill patients has become an integral part of every modern health care system, ensuing improved care and reduced mortality. Early recognition of severe medical and surgical illnesses, advanced prehospital care and organized immediate care in trauma centres led to a rise of ICU patients. Due to the underlying disease and its need for complex mechanical support for monitoring and treatment, it is often necessary to facilitate bed-side diagnostics. Immediate diagnostics are essential for a successful treatment of life threatening conditions, early recognition of complications and good quality of care. Management of ICU patients is incomprehensible without continuous and sophisticated monitoring, bedside ultrasonography, diverse radiologic diagnostics, blood gas analysis, coagulation and blood management, laboratory and other point-of-care (POC) diagnostic modalities. Moreover, in the time of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, particular attention is given to the POC diagnostic techniques due to additional concerns related to the risk of infection transmission, patient and healthcare workers safety and potential adverse events due to patient relocation. This review summarizes the most actual information on possible diagnostic modalities in critical care, with a special focus on the importance of point-of-care approach in the laboratory monitoring and imaging procedures.

Antithrombin and Its Role in Host Defense and Inflammation.

Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic heparin. However, AT levels drop in systemic inflammatory diseases. The reason for this decline is consumption by the coagulation system but also by immunological processes. Aside from the primarily known anticoagulant effects, AT elicits distinct anti-inflammatory signaling responses. It binds to structures of the glycocalyx (syndecan-4) and further modulates the inflammatory response of endothelial cells and leukocytes by interacting with surface receptors. Additionally, AT exerts direct antimicrobial effects: depending on AT glycosylation it can bind to and perforate bacterial cell walls. Peptide fragments derived from proteolytic degradation of AT exert antibacterial properties. Despite these promising characteristics, therapeutic supplementation in inflammatory conditions has not proven to be effective in randomized control trials. Nevertheless, new insights provided by subgroup analyses and retrospective trials suggest that a recommendation be made to identify the patient population that would benefit most from AT substitution. Recent experiment findings place the role of various AT isoforms in the spotlight. This review provides an overview of new insights into a supposedly well-known molecule.

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.