Dabigatran Reversal With Idarucizumab Preceding Thrombolysis in an Octogenarian Patient with Chronic Kidney Disease and Acute Stroke: A Case Report.

BACKGROUND AND PURPOSE: Reversing the effect of dabigatran among patients with atrial fibrillation is important to normalize coagulation profile among patients who develop serious hemorrhage from any source. However, such intervention always has the potential to cause a prothrombotic state. Among patients suspected of ischemic stroke, Idarucizumab, may be administered preceding thrombolysis. This is a considerable option when given during the critical phase of revascularization. METHODS: We report the case of an 84-year old, male, banker, known hypertensive with chronic renal disease. He has non valvular atrial fibrillation receiving Dabigatran at 75 mg twice daily and presented with symptoms of right-sided weakness, right hemisensory loss, facial asymmetry, and slurring of speech equating to National Institute of Health Stroke Scale (NIHSS) of 5. After coming into the hospital for a suspected stroke, 3 hours and 25 minutes after symptoms, complete reversal of Dabigatran with Idarucizumab was administered and intravenous thrombolysis was initiated 271 minutes post ictus. There was immediate improvement of the right upper extremity weakness and dysarthria 30 minutes post infusion. At 13 days post ictus, the patient was discharged with minimal right central facial palsy and right arm drift (NIHSS 2). Brain CT scan post revascularization did not reveal any hemorrhage and anticoagulant Apixaban 2.5 mg twice daily was started and maintained thereafter. Brain Magnetic Resonance Angiogram (MRA) showed complete recanalization of the left proximal MCA after 52 days. CONCLUSION: Our case showed the effectiveness and safety of giving Idarucizumab followed by thrombolysis in Dabigatran-treated atrial fibrillation with ischemic stroke. Based on this case, the procedure can be performed in an elderly population with chronic kidney disease when administered close to the limit of threshold for thrombolysis.

Asia-Pacific consensus statement on the optimal use of high-sensitivity troponin assays in acute coronary syndromes diagnosis: focus on hs-TnI.

OBJECTIVE: High-sensitivity troponin (hs-Tn) assays need to be applied appropriately to improve diagnosis and patient outcomes in acute coronary syndromes (ACS). METHODS: Experts from Asia Pacific convened in 2015 to provide data-driven consensus-based, region-specific recommendations and develop an algorithm for the appropriate incorporation of this assay into the ACS assessment and treatment pathway. RESULTS: Nine recommendations were developed by the expert panel: (1) troponin is the preferred cardiac biomarker for diagnostic assessment of ACS and is indicated for patients with symptoms of possible ACS; (2) hs-Tn assays are recommended; (3) serial testing is required for all patients; (4) testing should be performed at presentation and 3 hours later; (5) gender-specific cut-off values should be used for hs-Tn I assays; (6) hs-Tn I level >10 times the upper limit of normal should be considered to 'rule in' a diagnosis of ACS; (7) dynamic change >50% in hs-Tn I level from presentation to 3-hour retest identifies patients at high risk for ACS; (8) where only point-of-care testing is available, patients with elevated readings should be considered at high risk, while patients with low/undetectable readings should be retested after 6 hours or sent for laboratory testing and (9) regular education on the appropriate use of troponin tests is essential. CONCLUSIONS: We propose an algorithm that will potentially reduce delays in discharge by the accurate 'rule out' of non-ACS patients within 3 hours. Appropriate research should be undertaken to ensure the efficacy and safety of the algorithm in clinical practice, with the long-term goal of improvement of care of patients with ACS in Asia Pacific.

The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis.

Increasing evidence suggests that the development of pulmonary fibrosis is a Th2-mediated process. We hypothesized that the CC chemokines that are associated with a Th2 profile (CCL17 and CCL22) have an important role in the development of pulmonary fibrosis. We measured CCL17 and CCL22 during the pathogenesis of bleomycin-induced pulmonary fibrosis. We found that both CCL17 and CCL22 were significantly elevated through day 20 as compared with control mice. Peak expression of CCL22 preceded the peak levels of CCL17, as measured by real-time quantitative PCR. CCR4 is the receptor for CCL17 and CCL22 therefore, to further characterize the role of CCL17 and CCL22, we measured CCR4 mRNA in lung tissue of bleomycin-treated mice by real-time quantitative PCR. CCR4 was significantly elevated in bleomycin-treated mice as compared with control mice. Immunolocalization demonstrated that CCR4 was expressed predominantly on macrophages. Neutralization of CCL17, but not CCL22, led to a reduction in pulmonary fibrosis. Immunolocalization of bleomycin-treated lung tissue and human idiopathic pulmonary fibrosis tissue specimens showed that epithelial cells expressed CCL17. These findings demonstrate a central role for Th2 chemokines and the macrophage in the pathogenesis of pulmonary fibrosis and are further support for the role of a Th2 phenotype in the pathogenesis of pulmonary fibrosis.

CXCR2 is critical to hyperoxia-induced lung injury.

Hyperoxia-induced lung injury is characterized by infiltration of activated neutrophils in conjunction with endothelial and epithelial cell injury, followed by fibrogenesis. Specific mechanisms recruiting neutrophils to the lung during hyperoxia-induced lung injury have not been fully elucidated. Because CXCL1 and CXCL2/3, acting through CXCR2, are potent neutrophil chemoattractants, we investigated their role in mediating hyperoxia-induced lung injury. Under variable concentrations of oxygen, murine survival during hyperoxia-induced lung injury was dose dependent. Eighty percent oxygen was associated with 50% mortality at 6 days, while greater oxygen concentrations were more lethal. Using 80% oxygen, we found that lungs harvested at day 6 demonstrated markedly increased neutrophil sequestration and lung injury. Expression of CXCR2 ligands paralleled neutrophil recruitment to the lung and CXCR2 mRNA expression. Inhibition of CXC chemokine ligands/CXCR2 interaction using CXCR2(-/-) mice exposed to hyperoxia significantly reduced neutrophil sequestration and lung injury, and led to a significant survival advantage as compared with CXCR2(+/+) mice. These findings demonstrate that CXC chemokine ligand/CXCR2 biological axis is critical during the pathogenesis of hyperoxia-induced lung injury.

Imbalance in the expression of CXC chemokines correlates with bronchoalveolar lavage fluid angiogenic activity and procollagen levels in acute respiratory distress syndrome.

Diffuse alveolar damage is the histopathological hallmark of acute respiratory distress syndrome (ARDS) and is a stereotypic response to a variety of etiologies. Moreover, a significant proportion of ARDS survivors have residual pulmonary fibrosis and compromised pulmonary function. This suggests that the pathogenesis of diffuse alveolar damage that ultimately leads to the chronic fibrosis of ARDS has features of dysregulated repair exemplified by exaggerated intra-alveolar angiogenesis and fibrogenesis (i.e., fibroproliferation and deposition of extracellular matrix), leading to progressive alveolar fibrosis and impaired lung function. We obtained bronchoalveolar lavage fluid (BALF) from patients with ARDS or ventilated control patients and assessed CXC chemokine levels by ELISA. We found an imbalance in the expression of ELR(+) as compared with ELR(-) CXC chemokines from BALF of patients with ARDS as compared with controls. This imbalance correlated with angiogenic activity as assessed by the corneal micropocket assay. Furthermore, these levels correlated with both procollagen I and procollagen III levels in BALF. In contrast, while BALF levels of vascular endothelial growth factor were elevated, vascular endothelial growth factor did not appear to be significantly contributing to the angiogenic activity. These findings suggest that CXC chemokines have an important role in the fibroproliferative phase of ARDS via the regulation of angiogenesis.

Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis.

The initial stimulus for inflammatory cell recruitment and the mechanisms responsible for the perpetuation and evolution of chronic inflammation, granulation tissue formation, and fibrosis have not been fully elucidated. Although interleukin (IL)-13, a Th2 cytokine, has been shown to have direct effects on fibroblasts that support fibroproliferation, it is also a potent inducer of a novel CC chemokine, C10, which is chemotactic for mononuclear phagocytes. The macrophage/mononuclear phagocyte has been shown to have a role in the pathogenesis of pulmonary fibrosis, serving as an important source of growth factors that regulate extracellular matrix synthesis. In this study we demonstrate that IL-13 and C10 are elevated in the pathogenesis of bleomycin-induced pulmonary fibrosis. Neutralization of IL-13, but not IL-4, attenuated bleomycin-induced pulmonary fibrosis and levels of C10, suggesting that IL-13 has an important role in the development of pulmonary fibrosis. IL-13 is a potent inducer of C10 in vivo, and neutralization of C10 attenuated bleomycin-induced pulmonary fibrosis and intrapulmonary macrophage numbers. This suggests that IL-13 has a role in the development of pulmonary fibrosis that is independent of its direct effect on fibroblasts and is evidence for an interaction between Th2 cytokines and specific CC chemokines.