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  • In summary we have discovered the first examples of movement

    2021-10-09

    In summary, we have discovered the first examples of movement of Asp189 upon binding to fXa inhibitors. A series of novel and potent fXa inhibitors with a phenyltriazolinone P moiety were identified. Although the general binding mode compared to our previously-reported fXa inhibitors was maintained, a larger cavity to accommodate this P moiety was created by the movement of the Asp189 side chain. X-ray structures revealed an intricate network of H-bonds between the triazolinone and the enzyme including several structural water molecules. Acknowledgements
    Introduction In phase III trials, non-vitamin-K antagonist oral anticoagulants (NOACs) were non-inferior and safer than conventional anticoagulation therapy [1, 2]. Whether they Pregnenolone Carbonitrile are appropriate for the treatment of intermediate-high risk pulmonary embolism (THROMBI), regardless of risk stratification, remains undefined [1]. However, NOACs failure in venous thromboembolism has been reported in several clinical conditions [[3], [4], [5], [6], [7], [8], [9], [10]]. We report one patient with THROMBI involving apixaban loading dose failure, where successful thrombolysis was performed 12 h after the last apixaban dose. Importantly, despite PE severity, simplified pulmonary embolism severity index (sPESI) failed twice to stratify risk in two consecutive ED admissions [11]. Considering the limited evidence of NOACs efficacy in THROMBI [1, 2] and the lack of safety recommendations in patients on NOACs who require urgent thrombolysis [12, 13], we performed a systematic review.
    Case report
    Systematic review
    Discussion This case highlights three topics: Primarily, indirect and direct factor Xa inhibition did not improve extensive thrombus burden and RVD. Secondly, we present a possible strategy to perform safe thrombolysis in patients with THROMBI on apixaban. Ultimately, sPESI failed to stratify THROMBI [11]. To the best of our knowledge, the first two clinical scenarios have not been described. Parenteral and oral anticoagulation are the foundation of acute PE management [1, 2, [12], [13], [14], [15]]. However, given their lack of fibrinolytic activity, they do not dissolve existing thrombi and only prevent their propagation and growth [14]. In our patient, we observed indirect and direct factor Xa inhibitor failure to reduce thrombus burden and RVD; however, D-Dimer concentrations lowered, suggesting inactivation of fibrinolysis and coagulation system. Apixaban was restarted based on this observation and its efficacy and safety profile [1, 2, 12, 14, 15]. Considering the findings and the growing and understandable tendency of NOACs application [[3], [4], [5], [6], [7], [8], [9], [10]], we advocate caution in using NOACs for THROMBI out of a clinical trial setting until further data is available [16]. It could be that skipping one dose of apixaban and starting thrombolysis 12 h later in “stable patients” is a safe strategy as has been observed in ischemic stroke and atrial fibrillation patients [17] or when specific reversal agents are unavailable [18]. Finally, the European Society of Cardiology guidelines recommend bedside PESI or sPESI to identify low- to THROMBI [12]. However, PESI was designed as an epidemiological tool and not for PE decision-making [19]. Clinicians in EDs should be aware of the potential drawbacks of sPESI, as well as the best RVD biomarker which could strengthen connective tissue tool whose stratifying ability remains unknown. These therapeutic failures alert ED clinicians to the potential limitations of enoxaparin and NOACs therapy in cases with an extensive thrombus burden.
    Funding
    Declaration of interest
    Venous thromboembolism (VTE) is an important complication following total hip arthroplasty (THA) and total knee arthroplasty (TKA). In the absence of prophylactic treatment, the risk of an asymptomatic postoperative thromboembolic event is estimated to be approximately 50%, and the risk of a symptomatic event is estimated to be 5%-15% , . These procedures can also result in deep vein thrombosis (DVT), pulmonary embolism (PE), infection, and death . Asian patients aged ≥40 years had a significantly higher relative risk of developing a DVT, proximal DVT, and PE . Anticoagulants are recommended by the guidelines and routinely used after major orthopedic surgery to prevent VTE. Anticoagulants have been found to reduce the risk of thromboembolic events by approximately 50%-80% when used prophylactically . Both the American College of Chest Physicians and American Association of Orthopedic Surgeons guidelines for VTE prophylaxis recommend antithrombotic prophylaxis following THA and TKA , . However, although pharmacologic thromboprophylaxis in patients with THA or TKA may decrease the incidence of VTE and other thrombus-related events, the risk of major bleeding is increased , . A strong relationship between major bleeding and poor outcomes irrespective of the anticoagulant used has been demonstrated . Hence, the trade-off between fewer symptomatic PE and DVT with thromboprophylaxis vs increased major bleeding should be considered , .