Tranexamic acid in patients with traumatic brain injury: a meta-analysis.

BACKGROUND: We performed a meta-analysis to assess the effectiveness and safety of tranexamic acid in patients with traumatic brain injury (TBI). METHODS: We searched the literature for articles evaluating the effectiveness and safety of tranexamic acid (TXA) in TBI published between January 2012 and January 2021, and identified 8 studies with a total of 10860 patients: 5660 received TXA and 5200 served as controls. We used a dichotomous or continuous approach with a random or fixed-effect model to assess the efficacy and safety of TXA in TBI, and calculated the mean difference (MD) and odds ratio (OR) with the corresponding 95% confidence interval. RESULTS: In patients with TBI, early administration of TXA was associated with a greater relative benefit (MD -2.45; 95% CI = -4.78 to -0.12; p=0.04) and less total haematoma expansion (MD - 2.52; 95% CI = -4.85 to -0.19; p=0.03) compared to controls. There were no statistically significant differences in mortality (OR 0.94; 95% CI=0.85-1.03; p=0.18), presence of progressive haemorrhage (OR 0.75; 95% CI=0.56-1.01; p=0.06), need for neurosurgery (OR 1.15; 95% CI=0.66-1.98; p=0.63), high Disability Rating Scale score (OR 0.90; 95% CI=0.56-1.45; p=0.68), and incidence of ischaemic or thromboembolic complications (OR 1.34; 95% CI=0.33-5.46; p=0.68) between TBI patients treated with TXA and controls. CONCLUSIONS: Early administration of TXA in TBI patients may have a greater relative benefit and may inhibit haematoma expansion. There were no significant differences in mortality, presence of progressive haemorrhage, need for neurosurgery, high Disability Rating Scale score, and incidence of ischaemic or thromboembolic complications between TBI patients treated with TXA and controls. Further studies are needed to validate these results.

Techniques for navigating postsurgical adhesions: Insights into mechanisms and future directions.

Postsurgical adhesions are a common complication of surgical procedures that can lead to postoperative pain, bowel obstruction, infertility, as well as complications with future procedures. Several agents have been developed to prevent adhesion formation, such as barriers, anti-inflammatory and fibrinolytic agents. The Food and Drug Administration (FDA) has approved the use of physical barrier agents, but they have been associated with conflicting clinical studies and controversy in the clinical utilization of anti-adhesion barriers. In this review, we summarize the human anatomy of the peritoneum, the pathophysiology of adhesion formation, the current prevention agents, as well as the current research progress on adhesion prevention. The early cellular events starting with injured mesothelial cells and incorporating macrophage response have recently been found to be associated with adhesion formation. This may provide the key component for developing future adhesion prevention methods. The current use of physical barriers to separate tissues, such as Seprafilm®, composed of hyaluronic acid and carboxymethylcellulose, can only reduce the risk of adhesion formation at the end stage. Other anti-inflammatory or fibrinolytic agents for preventing adhesions have only been studied within the context of current research models, which is limited by the lack of in-vitro model systems as well as in-depth study of in-vivo models to evaluate the efficiency of anti-adhesion agents. In addition, we explore emerging therapies, such as gene therapy and stem cell-based approaches, that may offer new strategies for preventing adhesion formation. In conclusion, anti-adhesion agents represent a promising approach for reducing the burden of adhesion-related complications in surgical patients. Further research is needed to optimize their use and develop new therapies for this challenging clinical problem.

Oral Tranexamic Acid for the Treatment of Melasma: Evidence and Experience-Based Consensus Statement from Indian Experts.

Melasma, a chronic pigmentary skin condition mainly affecting the face, remains a challenge despite the availability of several options for treatment. Many melasma patients are not satisfied with treatment outcomes. Tranexamic acid (TXA), an anti-fibrinolytic drug has shown promising results in patients with melasma. Evidence from several clinical studies has surfaced on efficacy and tolerability of TXA in these patients. It can be used as monotherapy or adjuvant with other therapies. Currently, there is no published consensus or guideline document for its use in the treatment of melasma. TXA is available for oral use, topical use as well as an injection. In this article, a consensus of Indian experts is prepared based on the available literature and experience with use of oral TXA in melasma. This review article might help clinicians for use of oral TXA appropriately while treating melasma.

Tenecteplase in Acute Stroke: What About the Children?

Tenecteplase is replacing alteplase as the fibrinolytic agent of choice for the acute management of ischemic stroke in many adult stroke centers due to practical and pharmacokinetic advantages in the setting of similar outcomes. Although thrombolytic use is increasing for acute childhood stroke, there is very limited experience with tenecteplase in children for any indication, and importantly, there are no data on safety, dosing, or efficacy of tenecteplase for childhood stroke. Changes in fibrinolytic capacity over childhood, pediatric pharmacological considerations such as age-specific differences in drug clearance and volume of distribution, and practical aspects of drug delivery such as availability in children's hospitals may impact decisions about transitioning from alteplase to tenecteplase for acute pediatric stroke treatment. Pediatric and adult neurologists should prepare institution-specific guidelines and organize prospective data collection.

Short-Term Efficacy Outcomes of Tenecteplase versus Alteplase for Acute Ischemic Stroke: A Meta-Analysis of 5 Randomized Trials.

Tenecteplase (TNK) has been shown to be noninferior to Alteplase (ALT) for long term efficacy and safety outcomes. Whether this also applies to short term efficacy outcomes such as early clinical improvement and recanalization is unknown. To compare TNK and ALT regarding the short term efficacy outcomes: early neurological improvement and recanalization. The PRISMA was used to conduct a meta analysis, adapted to noninferiority analysis. The primary outcome was early (24-72 h) neurological improvement, defined as either NIHSS score 0 or reduction of at least 8 points compared to baseline. Recanalization was a secondary outcome. The noninferiority margin was set at 6.5%. Search strategy yielded 5 randomized clinical trials (1585 patients: 828 TNK, 757 ALT). Mean age was 70.8, 58.8% were men, mean baseline NIHSS was 7, and mean onset to treatment time was 148 min. Patients in intervention group received TNK at doses of 0.1 mg/kg (6.8%), 0.25 mg/kg (24.6%), and 0.4 mg/kg (68.6%), while all ALT patients received 0.9 mg/kg. In random effects meta analysis, TNK was noninferior to ALT for the primary outcome, early major neurological improvement (risk difference 8% in favor of TNK, 95% CI 1%-15%). Recanalization was also noninferior for the TNK compared to the ALT group (risk difference 9% in favor of TNK, 95% CI 6% to 23%). Fixed effects models yielded similarly noninferior results and signaled for a possible TNK superiority for both early neurological improvement and recanalization. TNK is noninferior to ALT at the short term efficacy outcomes: early neurological improvement and recanalization.

Dual function of a bumblebee (Bombus ignitus) serine protease inhibitor that acts as a microbicidal peptide and anti-fibrinolytic venom toxin.

In bee venoms, low-molecular-weight peptides, including serine protease inhibitors (SPIs), exhibit multifunctional activities. Although SPIs in bee venoms are relatively well known, those that function in both the body and secreted venom of bees are not well-characterized. In this study, we identified a bumblebee (Bombus ignitus) SPI (BiSPI) that displays microbicidal and anti-fibrinolytic activities. BiSPI was found to consist of a trypsin inhibitor-like domain containing a P1 site and ten cysteine residues. We observed that the BiSPI gene was ubiquitously transcribed in the body, including the venom glands. In correlation, the BiSPI protein was detected both in the body and secreted venom by using an antibody against a recombinant BiSPI peptide produced in baculovirus-infected insect cells. Recombinant BiSPI exhibited inhibitory activity against trypsin but not chymotrypsin and inhibited microbial serine proteases and plasmin but not elastase or thrombin. Moreover, recombinant BiSPI recognized carbohydrates and bound to fungi and gram-negative and gram-positive bacteria. Consistent with these properties, recombinant BiSPI exhibited microbicidal activities against bacteria and fungi through induction of structural damage by binding to the microbial surfaces. Additionally, recombinant BiSPI inhibited the plasmin-mediated degradation of human fibrin and was thus concluded to exhibit anti-fibrinolytic activity. Moreover, the peptide showed no effect on hemolysis. These findings demonstrate the dual function of BiSPI, which acts as a microbicidal peptide and anti-fibrinolytic venom toxin.

Two-dimensional transthoracic echocardiographic demonstration of reduction in fibrin content in purulent pericarditis following intrapericardial fibrinolytic agent administration.

We describe an adult patient who presented with purulent pericarditis (PP) in whom two-dimensional transthoracic echocardiography demonstrated a marked decrease in the area of the right ventricular (RV) wall together with the overlying fibrin following intrapericardial administration of a fibrinolytic agent. Documentation of this decrease by measurements performed and illustrated on two-dimensional images has not been reported previously in an adult patient with PP, to the best of our knowledge.

Antithrombotic Study and Identification of Metabolites in Leaf Extracts of Chaya [Cnidoscolus aconitifolius (Mill.) I.M. Johnst.].

In Mexico, Cnidoscolus aconitifolius (chaya) has been used to treat cardiovascular diseases (CVD). Because CVD are the number one cause of mortality, chaya use has become a health strategy. The aim of this study was to evaluate the antithrombotic activity and identify the metabolites in the most active extract. Aqueous (Aq), ethanolic (EtOH), acetonic (An), ethyl acetate (AcOEt), diethyl ether (Et2O), and hexanic (Hx) extracts were obtained. Platelet aggregation, phospholipase A2, prothrombin time (PT), activated partial thromboplastin time (aPTT), and clot lysis were evaluated. Metabolites were identified by gas chromatography-mass spectrometry (GC-MS). EtOH showed the greatest inhibition of platelet aggregation and phospholipase A2. Ac had the greatest effect on PT and aPTT. AcOEt had the greatest effect on clot lysis. EtOH, with the highest potential, was analyzed by GC-MS; fatty acids and triterpenes were identified. Thus, EtOH showed greater antiplatelet activity and other extracts showed moderate activity. This is a preliminary antithrombotic study. Future research will allow the development of nutraceuticals or functional ingredients for the prevention and treatment of thrombosis.

Anti-fibrinolytic activity of a metalloprotease inhibitor from bumblebee (Bombus ignitus) venom.

Bee venom is a mixture of bioactive components that include proteases and protease inhibitors. A metalloprotease inhibitor has been predicted to be a bumblebee-specific toxin in the venom proteome of Bombus terrestris; however, the identification and functional roles of bee venom metalloprotease inhibitors have not been previously determined. In this study, we identified a bumblebee (B. ignitus) venom metalloprotease inhibitor (BiVMPI) that exhibits anti-fibrinolytic activity. BiVMPI contains a trypsin inhibitor-like cysteine-rich domain that exhibits similarity to inducible metalloprotease inhibitor. Using an anti-BiVMPI antibody raised against a recombinant BiVMPI protein produced in baculovirus-infected insect cells, the presence of BiVMPI in the venom gland and secreted venom of B. ignitus worker bees was confirmed. The recombinant BiVMPI protein demonstrated inhibitory activity against a metalloprotease, trypsin, chymotrypsin, protease K, and plasmin, but not subtilisin A, elastase, or thrombin. Additionally, the recombinant BiVMPI bound to plasmin and inhibited the plasmin-mediated degradation of fibrin, demonstrating an anti-fibrinolytic role for BiVMPI as a bee venom metalloprotease inhibitor. Our results provide the first evidence for the identification and anti-fibrinolytic activity of a metalloprotease inhibitor from bee venom.

Nebulized tranexamic acid for recurring hemoptysis in critically ill patients: case series.

BACKGROUND: Hemoptysis is a clinical condition encountered in the emergency department (ED) and must be managed and investigated urgently to maintain the patient's hemostasis. The management of hemoptysis depends on treating the underlying cause. Tranexamic acid (TXA) is an anti-fibrinolytic drug used to systemically control bleeding. There are a few studies available that investigate the use of nebulized tranexamic acid for hemoptysis with contradictory results. Our paper demonstrates three cases where patients presented with significant hemoptysis and had significant improvement in symptoms following the administration of nebulized tranexamic acid. The overall need for blood transfusion was reduced. RESULTS: Three patients presented to the emergency room for evaluation of hemoptysis. All three patients had different underlying pathologies resulting in their hemoptysis and were monitored in the ICU. Initial conventional medical therapies including the correction of coagulopathy and discontinuing offending agents were utilized for treatment. After persistent symptoms, nebulized TXA at a dose of 500 mg three times a day was administered. The patients were all discharged from the hospital with improvement in their symptoms. CONCLUSION: Tranexamic acid may be considered in the treatment of hemoptysis regardless of the underlying cause. This may be utilized pending further workup and investigation into the underlying source of the bleeding.

Frequency and factors related to not receiving acute reperfusion therapy in patients with ST elevation myocardial infarction; a single specialty cardiac center.

OBJECTIVE: To determine the frequency of no reperfusion therapy, its reasons, hospital management and intermediate-term outcome s of ST- elevation my ocardial in farction patients . METHODS: The retrospective ambi-directional observational study was conducted at Tabba Heart Institute, Karachi, and comprised record of ST-elevation myocardial infarction patients without immediate reperfusion therapy with symptom onset time of 12 hours who presented between January 2013 and December 2017. Prospective follow-up of all patients was performed till June 2018. Coronary angiography, non-invasive stress tests, medications and late revascularisation were explored. Predictors of hospital mortality and major adverse cardiovascular events at follow-up were analysed. Data was analysed using SPSS 19. RESULTS: Of the 1977 records evaluated, 218(11%) patients of mean age 60.3±12.4 years did not receive immediate reperfusion therapy. Coronary angiography was done in 163(74.7%) patients of whom 45(27.6%) were taken for immediate procedure. Besides, 26 (11.9%) patients died during hospital stay. Predictors of hospital mortality were no revascularisation (odds ratio: 24.1, 95% confidence interval: 1.3-500), cardiogenic shock (odds ratio: 65, 95% confidence interval: 5.7-745) and tachycardia (odds ratio: 17, 95% confidence interval: 1.2-254.5) at presentation. Predictor of major adverse cardiovascular events was guideline-directed medical therapy (hazard ratio 2.6, 95% confidence interval: 1.16-6.2) at discharge, while revascularisation was not a significant predictor (p>0.05). CONCLUSION: A huge number of salvageable ST-elevation myocardial infarction patients failed to receive reperfusion therapy. There is a huge potential of improvement in ST-elevation myocardial infarction care in terms of increasing community awareness, prompt reperfusion therapy and usage of optimal medical therapy.

Evidence that Tenecteplase Is Noninferior to Alteplase for Acute Ischemic Stroke: Meta-Analysis of 5 Randomized Trials.

Background and Purpose- TNK (tenecteplase), a newer fibrinolytic agent, has practical delivery advantages over ALT (alteplase) that would make it a useful agent if noninferior in acute ischemic stroke treatment outcome. Accordingly, the most recent US American Heart Association/American Stroke Association acute ischemic stroke guideline recognized TNK as an alternative to ALT, but only based on informal consideration, rather than formal meta-analysis, of completed randomized control trials. Methods- Systematic literature search and formal meta-analysis were conducted per PRISMA guidelines (Preferred Reporting Items for Systemic Reviews and Meta-Analyses), adapted to noninferiority analysis. The primary outcome of freedom from disability (modified Rankin Scale score, 0-1) outcome at 3 m, and additional efficacy and safety outcomes, were analyzed. Results- Systematic search identified 5 trials enrolling 1585 patients (828 TNK, 757 ALT). Across all trials, mean age was 70.8, 58.5% male, baseline National Institutes of Health Stroke Scale mean 7.0, and time from last known well to treatment start mean 148 minutes. All ALT patients received standard 0.9 mg/kg dosing, while TNK dosing was 0.1 mg/kg in 6.8%, 0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%. For the primary end point, crude cumulative rates of disability-free (modified Rankin Scale score, 0-1) 3 m outcome were TNK 57.9% versus ALT 55.4%. Informal, random-effects meta-analysis, the risk difference was 4% (95% CI, -1% to 8%). The lower 95% CI bound fell well within the prespecified noninferiority margin. Similar results were seen for the additional efficacy end points: functional independence (modified Rankin Scale score, 0-2): crude TNK 71.9% versus ALT 70.5%, risk difference 2% (95% CI, -3% to 6%); and modified Rankin Scale shift analysis, common odds ratio 1.21 (95% CI, 0.93-1.57). For safety end points, lower event rates reduced power, but point estimates were also consistent with noninferiority Conclusions- Accumulated clinical trial data provides strong evidence that TNK is noninferior to ALT in the treatment of acute ischemic stroke. These findings provide formal support for the recent guideline recommendation to consider TNK an alternative to ALT.

Anti-fibrinolytic and anti-microbial activities of a serine protease inhibitor from honeybee (Apis cerana) venom.

Bee venom contains a variety of peptide constituents, including low-molecular-weight protease inhibitors. While the putative low-molecular-weight serine protease inhibitor Api m 6 containing a trypsin inhibitor-like cysteine-rich domain was identified from honeybee (Apis mellifera) venom, no anti-fibrinolytic or anti-microbial roles for this inhibitor have been elucidated. In this study, we identified an Asiatic honeybee (A. cerana) venom serine protease inhibitor (AcVSPI) that was shown to act as a microbial serine protease inhibitor and plasmin inhibitor. AcVSPI was found to consist of a trypsin inhibitor-like domain that displays ten cysteine residues. Interestingly, the AcVSPI peptide sequence exhibited high similarity to the putative low-molecular-weight serine protease inhibitor Api m 6, which suggests that AcVSPI is an allergen Api m 6-like peptide. Recombinant AcVSPI was expressed in baculovirus-infected insect cells, and it demonstrated inhibitory activity against trypsin, but not chymotrypsin. Additionally, AcVSPI has inhibitory effects against plasmin and microbial serine proteases; however, it does not have any detectable inhibitory effects on thrombin or elastase. Consistent with these inhibitory effects, AcVSPI inhibited the plasmin-mediated degradation of fibrin to fibrin degradation products. AcVSPI also bound to bacterial and fungal surfaces and exhibited anti-microbial activity against fungi as well as gram-positive and gram-negative bacteria. These findings demonstrate the anti-fibrinolytic and anti-microbial roles of AcVSPI as a serine protease inhibitor.

Engineering, expression and purification of a chimeric fibrin-specific streptokinase.

Streptokinase is a valuable fibrinolytic agent used to cope with myocardial infarction and brain stroke. Despite its high efficiency in dissolving blood clots, streptokinase (SK) has no specificity in binding fibrin, causing some problems such as internal bleedings following its administration. To make streptokinase fibrin specific and limit the fibrinolytic process to the clot location, we engineered a chimeric streptokinase by fusing the fibrin binding Kringle 2 domain of tissue plasminogen activator (TPA) to the streptokinase N-terminal end. The chimeric SK construct (KSK) with inserted Kringle 2 domain was cloned into pET28a expression vector. The expression of recombinant protein was carried out in Escherichia coli origami (DE3) and confirmed by SDS-PAGE and Western blotting analyses. We used the chromogenic substrate S-2251 method to assess the specific activities of the chimeric and control wild-type proteins. Then, the two proteins were added in amounts with equal activity to fibrin clots of identical size. Finally, the supernatant above the fibrin clots was collected and subjected to the chromogenic assay to analyze the specificity of the chimeric protein. The specific activities of the chimeric and wild-type proteins were found to be 0.06 U/mg and 0.07 U/mg, respectively. Because of the binding of the chimeric protein to fibrin, the mean specific activity was significantly lower in the KSK supernatant (0.01) compared with the control (approximately 0.06) (p < 0.05). Our in vitro results indicate that the chimeric streptokinase protein has strong fibrin-specific activity compared to the wild-type protein. However, further in vivo studies are needed to evaluate its potential fibrinolytic effects.

Secapin, a bee venom peptide, exhibits anti-fibrinolytic, anti-elastolytic, and anti-microbial activities.

Bee venom contains a variety of peptide constituents that have various biological, toxicological, and pharmacological actions. However, the biological actions of secapin, a venom peptide in bee venom, remain largely unknown. Here, we provide the evidence that Asiatic honeybee (Apis cerana) secapin (AcSecapin-1) exhibits anti-fibrinolytic, anti-elastolytic, and anti-microbial activities. The recombinant mature AcSecapin-1 peptide was expressed in baculovirus-infected insect cells. AcSecapin-1 functions as a serine protease inhibitor-like peptide that has inhibitory effects against plasmin, elastases, microbial serine proteases, trypsin, and chymotrypsin. Consistent with these functions, AcSecapin-1 inhibited the plasmin-mediated degradation of fibrin to fibrin degradation products, thus indicating the role of AcSecapin-1 as an anti-fibrinolytic agent. AcSecapin-1 also inhibited both human neutrophil and porcine pancreatic elastases. Furthermore, AcSecapin-1 bound to bacterial and fungal surfaces and exhibited anti-microbial activity against fungi and gram-positive and gram-negative bacteria. Taken together, our data demonstrated that the bee venom peptide secapin has multifunctional roles as an anti-fibrinolytic agent during fibrinolysis and an anti-microbial agent in the innate immune response.

Complications and management of attempted suicide by intrapleural injection of prallethrin.

We describe the unusual presentation and management of complications of intrapleural prallethrin injection in this case report. The pathologic process is distinct from the usual toxicity secondary to effect on ionic channels of the nervous system.