11 research outputs found
TAVR as Rescue Treatment for Prosthetic Heart Valve Endocarditis: Fortes Fortuna Adiuvat?
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t-PA Suppresses the Immune Response and Aggravates Neurological Deficit in a Murine Model of Ischemic Stroke
Introduction: Acute ischemic stroke (AIS) is a potent trigger of immunosuppression, resulting in increased infection risk. While thrombolytic therapy with tissue-type plasminogen activator (t-PA) is still the only pharmacological treatment for AIS, plasmin, the effector protease, has been reported to suppress dendritic cells (DCs), known for their potent antigen-presenting capacity. Accordingly, in the major group of thrombolyzed AIS patients who fail to reanalyze (>60%), t-PA might trigger unintended and potentially harmful immunosuppressive consequences instead of beneficial reperfusion. To test this hypothesis, we performed an exploratory study to investigate the immunomodulatory properties of t-PA treatment in a mouse model of ischemic stroke.Methods: C57Bl/6J wild-type mice and plasminogen-deficient (plg−/−) mice were subjected to middle cerebral artery occlusion (MCAo) for 60 min followed by mouse t-PA treatment (0.9 mg/kg) at reperfusion. Behavioral testing was performed 23 h after occlusion, pursued by determination of blood counts and plasma cytokines at 24 h. Spleens and cervical lymph nodes (cLN) were also harvested and characterized by flow cytometry.Results: MCAo resulted in profound attenuation of immune activation, as anticipated. t-PA treatment not only worsened neurological deficit, but further reduced lymphocyte and monocyte counts in blood, enhanced plasma levels of both IL-10 and TNFα and decreased various conventional DC subsets in the spleen and cLN, consistent with enhanced immunosuppression and systemic inflammation after stroke. Many of these effects were abolished in plg−/− mice, suggesting plasmin as a key mediator of t-PA-induced immunosuppression.Conclusion: t-PA, via plasmin generation, may weaken the immune response post-stroke, potentially enhancing infection risk and impairing neurological recovery. Due to the large number of comparisons performed in this study, additional pre-clinical work is required to confirm these significant possibilities. Future studies will also need to ascertain the functional implications of t-PA-mediated immunosuppression for thrombolyzed AIS patients, particularly for those with failed recanalization
Defining trauma-induced coagulopathy with respect to future implications for patient management : Communication from the SSC of the ISTH
Peer reviewedPostprin
Plasmin Generation Potential and Recanalization in Acute Ischaemic Stroke; an Observational Cohort Study of Stroke Biobank Samples
Rationale
More than half of patients who receive thrombolysis for acute ischaemic stroke fail to recanalize. Elucidating biological factors which predict recanalization could identify therapeutic targets for increasing thrombolysis success.
Hypothesis
We hypothesize that individual patient plasmin potential, as measured by in vitro response to recombinant tissue-type plasminogen activator (rt-PA), is a biomarker of rt-PA response, and that patients with greater plasmin response are more likely to recanalize early.
Methods
This study will use historical samples from the Barcelona Stroke Thrombolysis Biobank, comprised of 350 pre-thrombolysis plasma samples from ischaemic stroke patients who received serial transcranial-Doppler (TCD) measurements before and after thrombolysis. The plasmin potential of each patient will be measured using the level of plasmin-antiplasmin complex (PAP) generated after in-vitro addition of rt-PA. Levels of antiplasmin, plasminogen, t-PA activity, and PAI-1 activity will also be determined. Association between plasmin potential variables and time to recanalization [assessed on serial TCD using the thrombolysis in brain ischemia (TIBI) score] will be assessed using Cox proportional hazards models, adjusted for potential confounders.
Outcomes
The primary outcome will be time to recanalization detected by TCD(defined as TIBI ≥4). Secondary outcomes will be recanalization within 6-h and recanalization and/or haemorrhagic transformation at 24-h. This analysis will utilize an expanded cohort including ∼120 patients from the Targeting Optimal Thrombolysis Outcomes (TOTO) study.
Discussion
If association between proteolytic response to rt-PA and recanalization is confirmed, future clinical treatment may customize thrombolytic therapy to maximize outcomes and minimize adverse effects for individual patients
Interventional Reperfusion Strategies for Acute Pulmonary Embolism.
Acute pulmonary embolism (APE) is a common, potentially life-threatening cardiovascular emergency, and represents the third leading cause of cardiovascular mortality after myocardial infarction and stroke. Risk stratification is important to guide the management of APE, as an early reperfusion strategy is associated with improved clinical outcomes in specific high-risk conditions. Pulmonary artery reperfusion is commonly achieved by systemic intravenous administration of thrombolytic drugs, but catheter-directed thrombolysis (CDThr) and interventional techniques of catheter-based embolectomy provide novel therapeutic approaches with an improved risk-benefit ratio. Future trials will help to determine when to use these different devices in massive or sub-massive APE, and which patient population is likely to benefit from interventional treatment
Sex‐dependent effects of tranexamic acid on blood‐brain barrier permeability and the immune response following traumatic brain injury in mice
Tranexamic Acid Influences the Immune Response, but not Bacterial Clearance in a Model of Post-Traumatic Brain Injury Pneumonia
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Fibrinolysis shutdown in trauma: historical review and clinical implications.
Despite over a half-century of recognizing fibrinolytic abnormalities after trauma, we remain in our infancy in understanding the underlying mechanisms causing these changes, resulting in ineffective treatment strategies. With the increased utilization of viscoelastic hemostatic assays (VHAs) to measure fibrinolysis in trauma, more questions than answers are emerging. Although it seems certain that low fibrinolytic activity measured by VHA is common after injury and associated with increased mortality, we now recognize subphenotypes within this population and that specific cohorts arise depending on the specific time from injury when samples are collected. Future studies should focus on these subtleties and distinctions, as hypofibrinolysis, acute shutdown, and persistent shutdown appear to represent distinct, unique clinical phenotypes, with different pathophysiology, and warranting different treatment strategies
Recommended from our members
Fibrinolysis Shutdown in Trauma: Historical Review and Clinical Implications.
Despite over a half-century of recognizing fibrinolytic abnormalities after trauma, we remain in our infancy in understanding the underlying mechanisms causing these changes, resulting in ineffective treatment strategies. With the increased utilization of viscoelastic hemostatic assays (VHAs) to measure fibrinolysis in trauma, more questions than answers are emerging. Although it seems certain that low fibrinolytic activity measured by VHA is common after injury and associated with increased mortality, we now recognize subphenotypes within this population and that specific cohorts arise depending on the specific time from injury when samples are collected. Future studies should focus on these subtleties and distinctions, as hypofibrinolysis, acute shutdown, and persistent shutdown appear to represent distinct, unique clinical phenotypes, with different pathophysiology, and warranting different treatment strategies