Pulmonary embolism in the COVID-19 pandemic era: Importance of bedside electrocardiography, echocardiography and use of Tenecteplase.

Pulmonary embolism is a blockage in one of the pulmonary arteries in the lungs. Globally, it is the third most frequent acute cardiovascular syndrome behind myocardial infarction and stroke. This is a 43-yearold Nigerian diabetic man who had liposuction three weeks before presenting with sudden onset breathlessness, productive cough, chest pain, fever, inability to complete a sentence and inability to carry out his normal daily activities during this coronavirus 2019 (COVID-19) pandemic. He was tachypneic, tachycardic, hypotensive with rapidly dropping oxygen saturation (84%-86%, 80%-84%). This presented a diagnostic challenge which was rapidly resolved with bedside electrocardiography and echocardiography. A diagnosis of pulmonary embolism was sustained. Subsequent SARS-COV-2 PCRbased test was negative. He was successfully managed with an antithrombotic agent, tenecteplase, without any adverse events. Keywords: COVID-19, pulmonary embolism, tenecteplase, electrocardiography, echocardiography

AFM investigation of APAC (antiplatelet and anticoagulant heparin proteoglycan)

Antiplatelet and anticoagulant drugs are classified antithrombotic agents with the purpose to reduce blood clot formation. For a successful treatment of many known complex cardiovascular diseases driven by platelet and/or coagulation activity, the need of more than one antithrombotic agent is inevitable. However, combining drugs with different mechanisms of action enhances risk of bleeding. Dual anticoagulant and antiplatelet (APAC), a novel semisynthetic antithrombotic molecule, provides both anticoagulant and antiplatelet properties in preclinical studies. APAC is entering clinical studies with this new exciting approach to manage cardiovascular diseases. For a better understanding of the biological function of APAC, comprehensive knowledge of its structure is essential. In this study, atomic force microscopy (AFM) was used to characterize APAC according to its structure and to investigate the molecular interaction of APAC with von Willebrand factor (VWF), since specific binding of APAC to VWF could reduce platelet accumulation at vascular injury sites. By the optimization of drop-casting experiments, we were able to determine the volume of an individual APAC molecule at around 600 nm3, and confirm that APAC forms multimers, especially dimers and trimers under the experimental conditions. By studying the drop-casting behavior of APAC and VWF individually, we depictured their interaction by using an indirect approach. Moreover, in vitro and in vivo conducted experiments in pigs supported the AFM results further. Finally, the successful adsorption of APAC to a flat gold surface was confirmed by using photothermal-induced resonance, whereby attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) served as a reference method. Graphical abstract

Fc-Modified Kko: A Novel Therapeutic for Heparin-Induced Thrombocytopenia (HIT), Reversing Both the Thrombocytopenia and Thrombosis

Heparin induced thrombocytopenia (HIT) is an immunogenic prothrombotic disorder caused by antibodies that recognize human platelet factor 4 (PF4) complexed to polyanions. We had previously shown using chimeric constructs of hPF4 and mouse (m) PF4 and chimeras with the related chemokine, neutrophil-activating peptide-2 that there is a single antigenic locus on hPF4 in these complexes to which most HIT antibodies bind. KKO is a mouse monoclonal IgG2b k anti-hPF4/polyanion monoclonal antibody that mimics pathogenic antibodies that induce HIT and provokes thrombosis in a murine model of HIT. We previously established that specific hydrolysis of N-linked glycans in the Fc-region of KKO by endoglycosidase from Streptococcus pyogenes EndoS (Genovis) yields >97% deglycosylation on LC-MS/MS generating DGKKO. This modification has no significant effect on binding to PF4-heparin complexes as shown by ELISA and by dynamic light scattering, but abrogates FcgRIIA-mediated binding and platelet activation, and decreases complement activation as evaluated by flow cytometry. To examine if DGKKO reduces prothrombotic effects, we compared DGKKO with KKO in human microfluidic system lined with human umbilical vein cells (HUVECs) that are then photochemically injured and a murine model involving "HIT mice" (mice that express FcgRIIA and human PF4 and lack mouse PF4). Using the microfluidic system described above and infusing blood from healthy donors with added human PF4 (25 µg/ml) and KKO (50 µg/ml) or HIT IgG from three individuals with SRA-positive HIT (1mg/ml) resulted in increased platelet adherence to the injured endothelium (Figure 1). Addition of DGKKO (50 µg/ml) 15 minutes after addition of HIT antibodies eliminated platelet accumulation (Figure 1). In the HIT murine model, we found that intraperitoneal (IP, 200 µg/mice) or intravenous (IV, 20 µg/mice) DGKKO did not induce thrombocytopenia in HIT mice, but reversed the thrombocytopenia induced by either IP KKO (200 µg/mice) or HIT IgG (1 mg/mice) even when the DGKKO is given 6 hrs after HIT induction (Figure 2A). We used an intravital cremaster laser arteriole injury model in HIT mice to study the efficacy of DGKKO as an antithrombotic agent. We found that unlike KKO that enhances growth of established thrombi in these mice, DGKKO significantly reversed the size of the observed thrombi (Figure 2B). These studies suggest that DGKKO obstructs the HIT antigenic site recognized by HIT antibodies and leads to a reversal of thrombocytopenia and thrombus size. Additional studies are underway to examine if DGKKO can be used as a monotherapy or adjunctive therapy in the murine model of HIT thrombosis. Figure 1 Figure 1. Disclosures Cines: Rigel: Consultancy; Dova: Consultancy; Treeline: Consultancy; Arch Oncol: Consultancy; Jannsen: Consultancy; Taventa: Consultancy; Principia: Other: Data Safety Monitoring Board.

P.075 Incidence of Stroke Associated With Antithrombotic Agent Interruption

Background: Antithrombotic medications are used in the primary and secondary prevention of ischemic stroke. Previous studies have identified that up to 5.2% of ischemic strokes are associated with antithrombotic interruption, leading to significant mortality and healthcare burden. Our study aims to identify the prevalence of ischemic strokes presenting to a regional stroke centre associated with antithrombotic interruption, and to understand common reasons for medication interruption. Methods: A retrospective chart review was performed, which included 193 patients with ischemic stroke presenting to Greater Niagara General Hospital from January 2018-December 2019. Baseline demographics were recorded and patient medical records were reviewed for evidence of antithrombotic interruptions. Results: Table 1. Conclusions: Our cohort identified a significant proportion (8.3%) of ischemic strokes with documented antithrombotic interruption. Most common reasons for interruption were non-adherence and discontinuation due to previous adverse event. The results identify possible areas for improvement within patient education and safe re-initiation of antithrombotics following adverse events.

Comparative study of subdural drain (SDD) versus sub periosteal drain (SPD) in treating patient with chronic subdural hematoma (CSDH)

Background: Chronic subdural hematoma (CSDH) is common neurosurgical condition encountered in daily practice. Burr holes evacuation is standard treatment for symptomatic cases. Both subdural drain (SDD) and subperiosteal drain (SPD) have been reported to lower the recurrence rate when used in conjunction with burr holes. A randomized controlled trials were done to see if there were any differences in clinical and radiographic outcomes between the two types of drains. Methods: A total of 42 CSDH patients were enrolled and allocated to one of two groups: SDD (n = 21) or SPD (n = 21). Demographic data, perioperative imaging characteristics, clinical outcome, and recurrence rate were recorded for comparison. Results: In both groups, demographic characteristics such as sex ratio, mean age of patients, concomitant disease, and antithrombotic agent use were similar. At 6 months, 20 (95.2%) and 21 (100%) cases in the SDD and SPD groups, respectively, had a favorable outcome (mRS 0–3). Complete hematoma resolution at 6 months was achieved in 21 (100%) and 19 (90.5%) cases of the SDD and SPD groups, respectively. The amount of drain within 48 h was not difference between the two groups. None of the SDD recurred, but two of the SPD group did, necessitating reoperation, which had no effect on the final outcome. Conclusion: These findings indicate that the drain type (SDD or SPD) has no effect on the outcome. The surgeon’s preference determines which procedure is used. Except in symptomatic circumstances, routine postoperative imaging may not be required.

Clinical outcomes of surgical embolectomy versus catheter-directed thrombolysis for acute limb ischemia: a nationwide cohort study

In Taiwan, the outcomes of acute limb ischemia have yet to be investigated in a standardized manner. In this study, we compared the safety, feasibility and outcomes of acute limb ischemia after surgical embolectomy or catheter-directed therapy in Taiwan. This study used data collected from the Taiwan’s National Health Insurance Database (NHID) and Cause of Death Data between the years 2000 and 2015. The rate ratio of all-cause in-hospital mortality and risk of amputation during the same period of hospital stay were estimated using Generalized linear models (GLM). There was no significant difference in mortality risk between CDT and surgical intervention (9.5% vs. 10.68%, adjusted rate ratio (95% CI): regression 1.0 [0.79–1.27], PS matching 0.92 [0.69–1.23]). The risk of amputation was also comparable between the two groups. (13.59% vs. 14.81%, adjusted rate ratio (95% CI): regression 0.84 [0.68–1.02], PS matching 0.92 [0.72–1.17]). Age (p < 0.001) and liver disease (p = 0.01) were associated with higher mortality risks. Heart failure (p = 0.03) and chronic or end-stage renal disease (p = 0.03) were associated with higher amputation risks. Prior antithrombotic agent use (p = 0.03) was associated with a reduced risk of amputation. Both surgical intervention and CDT are effective and feasible procedures for patients with ALI in Taiwan.

Unintentional guideline deviations in hospitalized patients with two or more antithrombotic agents: an intervention study

Purpose Treatment schedules for antithrombotic therapy are complex, and there is a risk of inappropriate prescribing or continuation of antithrombotic therapy beyond the intended period of time. The primary aim of this study was to determine the frequency of unintentional guideline deviations in hospitalized patients. Secondary aims were to determine whether the frequency of unintentional guideline deviations decreased after intervention by a pharmacist, to determine the acceptance rate of the interventions and to determine the type of interventions. Methods We performed a non-controlled prospective intervention study in three teaching hospitals in the Netherlands. We examined whether hospitalized patients who used the combination of an anticoagulant plus at least one other antithrombotic agent had an unintentional guideline deviation. In these cases, the hospital pharmacist contacted the physician to assess whether this deviation was intentional. If the deviation was unintentional, a recommendation was provided how to adjust the antithrombotic regimen according to guideline recommendations. Results Of the 988 included patients, 407 patients had an unintentional guideline deviation (41.2%). After intervention, this was reduced to 22 patients (2.2%) (p < 0.001). The acceptance rate of the interventions was 96.6%. The most frequently performed interventions were discontinuation of an low molecular weight heparin in combination with a direct oral anticoagulant and discontinuation of an antiplatelet agent when there was no indication for the combination of an antiplatelet agent and an anticoagulant. Conclusion A significant number of hospitalized patients who used an anticoagulant plus one other antithrombotic agent had an unintentional guideline deviation. Intervention by a pharmacist decreased unintentional guideline deviations.

Role of combining anticoagulant and antiplatelet agents in COVID-19 treatment: a rapid review

Although primarily affecting the respiratory system, COVID-19 causes multiple organ damage. One of its grave consequences is a prothrombotic state that manifests as thrombotic, microthrombotic and thromboembolic events. Therefore, understanding the effect of antiplatelet and anticoagulation therapy in the context of COVID-19 treatment is important. The aim of this rapid review was to highlight the role of thrombosis in COVID-19 and to provide new insights on the use of antithrombotic therapy in its management. A rapid systematic review was performed using preferred reporting items for systematic reviews. Papers published in English on antithrombotic agent use and COVID-19 complications were eligible. Results showed that the use of anticoagulants increased survival and reduced thromboembolic events in patients. However, despite the use of anticoagulants, patients still suffered thrombotic events likely due to heparin resistance. Data on antiplatelet use in combination with anticoagulants in the setting of COVID-19 are quite scarce. Current side effects of anticoagulation therapy emphasise the need to update treatment guidelines. In this rapid review, we address a possible modulatory role of antiplatelet and anticoagulant combination against COVID-19 pathogenesis. This combination may be an effective form of adjuvant therapy against COVID-19 infection. However, further studies are needed to elucidate potential risks and benefits associated with this combination.

Ramatroban, an orally bioavailable immunomodulator and antithrombotic agent for treatment of COVID-19 disease: A Case Report

SARS-CoV-2 pneumonia and COVID-19 disease are characterized by a maladaptive immune response and prothrombotic state. The Spike protein of SARS-CoV-2 virus unleashes a storm of lipid mediators with very high levels of thromboxane B2 and prostaglandin D2 in the bronchoalveolar lavage fluid. DPr2 receptors for prostaglandin D2 and TPr receptors for thromboxane A2 have been proposed as therapeutic targets in COVID-19 in order to decrease viral load and inhibit platelet dependent thrombosis, respectively. Ramatroban is an oral, dual receptor antagonist of the DPr2 and TPr receptors with established safety profile, having been used in Japan for the treatment of allergic rhinitis for over 20 years. We report two patients, an 88-year-old woman and a 31-year-old man, both with COVID-19 pneumonia who were successfully treated in ambulatory setting with oral ramatroban, leading to rapid improvement in oxygen saturation from about 80–82% to about 90–95% over 24–48 hours followed by gradual recovery from the disease. The mechanism of action of ramatroban and its efficacy reported here supports clinical trials on this drug as a potential treatment for COVID-19.