Platelet-to-neutrophil ratio predicts hemorrhagic transformation and unfavorable outcomes in acute ischemic stroke with intravenous thrombolysis.

BACKGROUND: Acute ischemic stroke (AIS) retains a notable stance in global disease burden, with thrombolysis via recombinant tissue plasminogen activator (rtPA) serving as a viable management approach, albeit with variable outcomes and the potential for complications like hemorrhagic transformation (HT). The platelet-to-neutrophil ratio (P/NR) has been considered for its potential prognostic value in AIS, yet its capacity to predict outcomes following rtPA administration demands further exploration. AIM: To elucidate the prognostic utility of P/NR in predicting HT and clinical outcomes following intravenous rtPA administration in AIS patients. METHODS: Data from 418 AIS patients treated with intravenous rtPA at Thammasat University Hospital from January 2018 to June 2021 were retrospectively analyzed. The relationship between P/NR and clinical outcomes [early neurological deterioration (E-ND), HT, delayed ND (D-ND), and 3-mo outcomes] was scrutinized. RESULTS: Notable variables, such as age, diabetes, and stroke history, exhibited statistical disparities when comparing patients with and without E-ND, HT, D-ND, and 3-mo outcomes. P/NR prognostication revealed an optimal cutoff of 43.4 with a 60.3% sensitivity and a 52.5% specificity for 90-d outcomes. P/NR prognostic accuracy was statistically significant for 90-d outcomes [area under the curve (AUC) = 0.562], D-ND (AUC = 0.584), and HT (AUC = 0.607). CONCLUSION: P/NR demonstrated an association with adverse 3-mo clinical outcomes, HT, and D-ND in AIS patients post-rtPA administration, indicating its potential as a predictive tool for complications and prognoses. This infers that a diminished P/NR may serve as a novel prognostic indicator, assisting clinicians in identifying AIS patients at elevated risk for unfavorable outcomes following rtPA therapy.

A single-center study of reference intervals for TAT, PIC, TM and t-PAIC in healthy older Chinese adults.

OBJECTIVE: To explore the distribution of thrombin-antithrombin complex (TAT), plasmin-α2-antiplasmin inhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) in healthy older Chinese adults, and establish the reference intervals (RIs). METHODS: The Biotech Shine i2900 chemiluminescence immune assay was used to measure the plasma concentrations of TAT, PIC, TM, and t-PAIC in 1628 adults ≥ 60 years. The RIs were established using the 2.5th and 97.5th percentiles of the distribution. RESULTS: TAT levels were lower in males than females across all ages. Differences between the ages of 60-79 and ≥ 80 in both sex groups were statistically significant, with an upward trend with age. PIC levels showed no difference between the sexes but increased with age in both groups. TM levels did not differ between the sex groups, with slight fluctuation with age. The level in females aged 60-69 was slightly higher than that in the other groups; the difference was statistically significant. T-PAIC levels were not significantly different between the sex groups, with less fluctuation with sex and age. The level in males ≥ 80 years old was slightly lower than that in the other groups; the difference was statistically significant. The RIs for all markers in healthy older Chinese adults were determined and statistically reported by age and sex. For TAT, the RIs for males aged 60-79 and ≥ 80 are 0.51-2.30 ng/mL and 0.88-3.72 ng/mL, respectively, whereas for females aged 60-79 and ≥ 80, the RIs are 0.68-2.82 ng/mL and 1.02-3.67 ng/mL, respectively. For PIC, the RIs for the age groups 60-69, 70-79, and ≥ 80 are 0.10-0.89 µg/mL, 0.12-1.00 µg/mL, and 0.21-1.04 µg/mL, respectively. The RI of TM for females aged 60-69 is 3.32-13.22 TU/mL, whereas it is 2.96-13.26 TU/mL for the other groups. The RI of t-PAIC for males aged ≥ 80 is 1.63-10.68 ng/mL, whereas it is 2.33-11.34 ng/mL for the other groups. CONCLUSIONS: Discrepancies exist in thrombus markers among different sex and age groups. The RIs of TAT, PIC, TM and t-PAIC for healthy older Chinese adults were successfully established.

The influence of 4G/5G polymorphism in the plasminogen-activator-inhibitor-1 promoter on COVID-19 severity and endothelial dysfunction.

Introduction: Plasminogen activator inhibitor-1 (PAI-1) is linked to thrombosis and endothelial dysfunction in severe COVID-19. The +43 G>A PAI-1 and 4G/5G promoter polymorphism can influence PAI-1 expression. The 4G5G PAI-1 promoter gene polymorphism constitutes the 4G4G, 4G5G, and 5G5G genotypes. However, the impact of PAI-1 polymorphisms on disease severity or endothelial dysfunction remains unclear. Methods: Clinical data, sera, and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients were studied. Results: Comorbidities and clinical biomarkers did not correlate with genotypes in either polymorphism. However, differences between fibrinolytic factors and interleukin-1ß (IL-1ß) were identified in genotypes of the 4G/5G but not the 43 G>A PAI polymorphism. Patients with the 4G4G genotype of the 4G/5G polymorphism showed high circulating PAI-1, mainly complexed with plasminogen activators, and low IL-1ß and plasmin levels, indicating suppressed fibrinolysis. NFκB was upregulated in PBMCs of COVID-19 patients with the 4G4G genotype. Discussion: Mechanistically, IL-1ß enhanced PAI-1 expression in 4G4G endothelial cells, preventing the generation of plasmin and cleavage products like angiostatin, soluble uPAR, and VCAM1. We identified inflammation-induced endothelial dysfunction coupled with fibrinolytic system overactivation as a risk factor for patients with the 5G5G genotype.

Differences in Acute Expression of Matrix Metalloproteinases-9, 3, and 2 Related to the Duration of Brain Ischemia and Tissue Plasminogen Activator Treatment in Experimental Stroke.

Matrix metalloproteinases (MMPs) such as MMP-9, 3, and 2 degrade the cellular matrix and are believed to play a crucial role in ischemic stroke. We examined how the duration of ischemia (up to 4 h) and treatment with recombinant tissue plasminogen activator altered the comparative expression of these MMPs in experimental ischemic stroke with reperfusion. Both prolonged ischemia and r-tPA treatment markedly increased MMP-9 expression in the ischemic hemisphere (all p < 0.0001). The duration of ischemia and r-tPA treatment also significantly increased MMP-2 expression (p < 0.01-0.001) in the ischemic hemisphere (p < 0.01) but to a lesser degree than MMP-9. In contrast, MMP-3 expression significantly decreased in the ischemic hemisphere (p < 0.001) with increasing duration of ischemia and r-tPA treatment (p < 0.05-0001). MMP-9 expression was prominent in the vascular compartment and leukocytes. MMP-2 expression was evident in the vascular compartment and MMP-3 in NeuN+ neurons. Prolonging the duration of ischemia (up to 4 h) before reperfusion increased brain hemorrhage, infarction, swelling, and neurologic disability in both saline-treated (control) and r-tPA-treated mice. MMP-9 and MMP-2 expression were significantly positively correlated with, and MMP-3 was significantly negatively correlated with, infarct volume, swelling, and brain hemorrhage. We conclude that in experimental ischemic stroke with reperfusion, the duration of ischemia and r-tPA treatment significantly altered MMP-9, 3, and 2 expression, ischemic brain injury, and neurological disability. Each MMP showed unique patterns of expression that are strongly correlated with the severity of brain infarction, swelling, and hemorrhage. In summary, in experimental ischemic stroke in male mice with reperfusion, the duration of ischemia, and r-tPA treatment significantly altered the immunofluorescent expression of MMP-9, 3, and 2, ischemic brain injury, and neurological disability. In this model, each MMP showed unique patterns of expression that were strongly correlated with the severity of brain infarction, swelling, and hemorrhage.

Paclitaxel and Vinblastine Increase Plasminogen Activator Inhibitor-1 Production in Human Breast Cancer MCF-7 Cells but Not MDA-MB-231 Cells.

Cancer chemotherapy increases the risk of thrombosis; however, the mechanisms underlying this thrombosis are not completely understood. Plasminogen activator inhibitor (PAI)-1 is a key molecule in the fibrinolytic system that inhibits tissue plasminogen activator and urokinase, which converts plasminogen into plasmin; therefore, excess PAI-1 increases the risk of thrombosis. In this study, we investigated whether temporary treatment of the human luminal A-type breast cancer cell line MCF-7 with antitumor drugs clinically used for breast cancer therapy promotes PAI-1 production. Treatment of MCF-7 cells with paclitaxel (PTX), a microtubule-stabilizing antitumor drug, at 1 µM for 2 h elevated the PAI-1 concentration of the conditioned medium at 48 h after treatment but not in those treated with tamoxifen and cyclophosphamide. Microtubule assembly inhibitors vinblastine (VBT) and vincristine (VCT) also increased the PAI-1 concentration in the conditioned medium. PAI-1 (SERPINE1) expression was upregulated in MCF-7 cells after PTX, VBT, and VCT treatment; this increase in expression persisted for eight days. In contrast, PAI-1 production in MDA-MB-231 cells treated with PTX, VBT, or VCT did not increase with increasing PAI-1 concentration. This study demonstrated that temporary low-dose treatment with microtubule-associated anticancer drugs increased PAI-1 release from MCF-7 cells but not from MDA-MB-231 cells. These results indicate that chemotherapy against luminal A-type breast cancer using microtubule-associated drugs may cause thrombosis through the inhibition of the fibrinolytic system by PAI-1.

The changes of tPA/PAI-1 system are associated with the ratio of BDNF/proBDNF in major depressive disorder and SSRIs antidepressant treatment.

Increasing evidence demonstrates that brain-derived neurotrophic factor (BDNF) can be regarded as a biomarker for major depression. Our previous work found that the ratio of mature BDNF (mBDNF) to precursor-BDNF (proBDNF) was a pivotal factor in the pathogenesis of major depressive disorder (MDD). But the mechanism behind the ratio is still obscure. Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) both play essential roles in depression by regulating the ratio of BDNF/proBDNF. In present study, we analyzed BDNF, proBDNF, tPA and PAI-1 in the peripheral blood in 57 MDD patients pre- and post-treatment and in 57 healthy controls. We verified that BDNF and tPA levels were significantly decreased, whereas proBDNF and PAI-1 levels elevated obviously in MDD group pre-treatment. And after 4 weeks SSRIs treatment, the BDNF and tPA levels increased while the proBDNF and PAI-1 levels reduced. The MDD pre-treatment group had the lowest ratio of BDNF to proBDNF compared to MDD post-treatment group and control group. Though the ratio of tPA/PAI-1 in MDD pre-treatment had not reached the significance, it was still the lowest one among the three groups. The combination of tPA + PAI + BDNF showed the best diagnostic value for MDD. In summary, our data suggested that the interaction between tPA and PAI-1 implicated to the MDD and the antidepressant treatment which might through regulating the BDNF/proBDNF ratio. The combination of tPA, PAI-1 and BDNF might offer a helpful way for MDD diagnosis.

Regulation of macrophage fibrinolysis during venous thrombus resolution.

BACKGROUND: Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a serious cardiovascular disease with significant mortality and morbidity. Clinically, patients with faster resolution of a venous thrombi have improved prognosis. Urokinase-plasminogen activator (uPA), produced by macrophages, is a key mediator of fibrinolysis required for resolving venous thrombi and restoring vascular integrity. The major macrophage protein, plasminogen activator inhibitor type-2 (PAI-2), was originally identified as an inhibitor of uPA and is implicated in the modulation of pathways affecting fibrinolytic uPA activity, however its direct role in blocking uPA-mediated clot lysis is not known. OBJECTIVE: To determine the contribution of macrophage PAI-2 in inhibiting uPA-mediated fibrinolysis during resolution of DVT. METHODS: Using a murine model of venous thrombosis and resolution, we determined histological changes and molecular features of fibrin degradation in venous thrombi from WT mice and mice genetically deficient in PAI-2 and PAI-1, and determined the fibrinolytic activities of macrophages from these genotypes ex vivo. RESULTS: Acceleration of venous thrombus resolution by PAI-2-/- mice increases fibrin degradation in venous thrombi showing a pattern similar to genetic deficiency of PAI-1, the major attenuator of fibrinolysis. PAI-2 deficiency was not associated with increased macrophage infiltration into thrombi or changes in macrophage PAI-1 expression. uPA-initiated fibrinolysis by macrophages in vitro could be accelerated by PAI-1 deficiency, but not PAI-2 deficiency. CONCLUSION: PAI-2 has an alternate anti-fibrinolytic activity that is macrophage uPA independent, where PAI-1 is the dominant uPA inhibitor during DVT resolution.

Tissue plasminogen activator for acute branch atheromatous disease exhibits transient improvement and worsening.

BACKGROUND: Tissue plasminogen activator (tPA) is an effective treatment for acute ischemic stroke. Although initial improvement is observed when administered for branch atheromatous disease (BAD), some cases subsequently worsen. Clinical data on the characteristics of these patients is lacking, and the benefits of tPA are unclear. OBJECTIVE: To analyze rebound cases and elucidate the clinical characteristics and outcomes associated with tPA administration in BAD. METHODS: This multicenter retrospective study was conducted in Japan. Worsening after initial improvement of a condition is termed as rebound, and such cases were compared with other types of ischemic stroke in patients with and without rebound. The characteristics of patients with BAD who rebounded were examined. RESULTS: The study included 93 patients. Among the patients who were administered tPA, the NIHSS scores at 24 h and 7 days post-tPA were significantly higher in patients with BAD than in patients with other types of infarcts. The group with BAD exhibited a significantly higher rate of rebound than other groups (37.5 % vs. 0 %, P < 0.001). However, no differences were observed in outcomes between patients who experienced rebound after tPA administration and those who did not. CONCLUSIONS: Reevaluation and changing the strategy of tPA use in patients with BAD may be necessary. However, this study does not totally discourage its use, as specific patients can benefit.

The islet tissue plasminogen activator/plasmin system is upregulated with human islet amyloid polypeptide aggregation and protects beta cells from aggregation-induced toxicity.

AIMS/HYPOTHESIS: Apart from its fibrinolytic activity, the tissue plasminogen activator (tPA)/plasmin system has been reported to cleave the peptide amyloid beta, attenuating brain amyloid deposition in Alzheimer's disease. As aggregation of human islet amyloid polypeptide (hIAPP) is toxic to beta cells, we sought to determine whether activation of the fibrinolytic system can also reduce islet amyloid deposition and its cytotoxic effects, which are both observed in type 2 diabetes. METHODS: The expression of Plat (encoding tPA) and plasmin activity were measured in isolated islets from amyloid-prone hIAPP transgenic mice or non-transgenic control islets expressing non-amyloidogenic mouse islet amyloid polypeptide cultured in the absence or presence of the amyloid inhibitor Congo Red. Plat expression was also determined in hIAPP-treated primary islet endothelial cells, bone marrow-derived macrophages (BMDM) and INS-1 cells, in order to determine the islet cell type(s) producing tPA in response to hIAPP aggregation. Cell-free thioflavin-T assays and MS were used to respectively monitor hIAPP aggregation kinetics and investigate plasmin cleavage of hIAPP. Cell viability was assessed in INS-1 beta cells treated with hIAPP with or without plasmin. Finally, to confirm the findings in human samples, PLAT expression was measured in freshly isolated islets from donors with and without type 2 diabetes. RESULTS: In isolated islets from transgenic mice, islet Plat expression and plasmin activity increased significantly with the process of amyloid deposition (p≤0.01, n=5); these effects were not observed in islets from non-transgenic mice and were blocked by Congo Red (p≤0.01, n=4). In response to hIAPP exposure, Plat expression increased in BMDM and INS-1 cells vs vehicle-treated cells (p≤0.05, n=4), but not in islet endothelial cells. Plasmin reduced hIAPP fibril formation in a dose-dependent manner in a cell-free system, and restored hIAPP-induced loss of cell viability in INS-1 beta cells (p≤0.01, n=5). Plasmin cleaved monomeric hIAPP, inducing a rapid decrease in the abundance of full-length hIAPP and the appearance of hIAPP 1-11 and 12-37 fragments. hIAPP 12-37, which contains the critical amyloidogenic region, was not toxic to INS-1 cells. Finally, PLAT expression was significantly increased by 2.4-fold in islets from donors with type 2 diabetes (n=4) vs islets from donors without type 2 diabetes (n=7) (p≤0.05). CONCLUSIONS/INTERPRETATION: The fibrinolytic system is upregulated in islets with hIAPP aggregation. Plasmin rapidly degrades hIAPP, limiting its aggregation into amyloid and thus protecting beta cells from hIAPP-induced toxicity. Thus, increasing islet plasmin activity might be a strategy to limit beta cell loss in type 2 diabetes.

Association between PAI-1 4G/5G genotype and residual thrombus in acute mesenteric venous thrombosis.

OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1) is the most important inhibitor of plasminogen activator. The functional 4G/5G polymorphism of the gene coding for PAI-1 may affect PAI-1 plasmatic activity, influencing the imbalance between coagulation and fibrinolysis cascades. In this study, we investigated the association between the PAI-1 4G/5G genotype and the development and residual thrombus of acute primary mesenteric venous thrombosis (MVT). METHODS: The clinical data of 34 patients who underwent acute primary MVT were retrospectively reviewed. Fluorescence in situ hybridization was used to determine if patients had the 4G/5G polymorphism in the promoter of the PAI-1 gene. Patients were stratified according to the genotype of PAI-1. RESULTS: 11 patients (32.3%) were homozygous for the 4G genotype, 23 patients (67.6%) were non-homozygous for the 4G genotype (5G/5G). The extent of thrombosis was not correlated with the PAI-4G/5G polymorphism. After a mean follow-up of 16.6 ± 10.4 months, the 4G/4G genotype had a significantly larger thrombus burden (p < 0.05). 54% of patients in the 4G/4G genotype group had no lessening in the degree of mesenteric venous thrombosis, significantly higher than other patients (4G/5G + 5G/5G genotypes) (p < 0.05). CONCLUSION: The PAI-1 4G/4G predicts residual thrombus of mesenteric veins after the acute phase.

Poria cocos Extract Alleviates tPA-Induced Hemorrhagic Transformation after Ischemic Stroke through Regulation of Microglia M1/M2 Phenotypes Polarization.

Delayed thrombolytic therapy with tissue plasminogen activator (tPA), the only FDA-approved drug for ischemic stroke, can cause catastrophic hemorrhagic transformation (HT) after ischemic stroke. However, it remains largely unknown how microglial polarization dynamically changes in HT. Poria cocos is a widely used functional edible fungus in Asia and has been used for more than 2000 years as a food and medicine in China. Our preliminary study found that P. cocos extract (PCE) significantly reduced the volume of cerebral infarction. We performed the effects of PCE on tPA-induced HT in rat models of autologous thromboembolism middle cerebral artery occlusion in vivo and BV-2 cells injured by oxygen-glucose deprivation/reperfusion in vitro. Hemorrhage test and triphenyltetrazolium chloride staining were performed to examine the efficiency of PCE. The expression level of proteins associated with microglia polarization was detected using Western blotting and immunofluorescence staining. Small interfering RNA transfection reveals the regulatory mechanism of PCE on microglia polarization. PCE plus tPA reduced hemorrhage and infarct volumes after ischemic stroke. During tPA-induced HT, M1 microglia increased over time from 3 days onward and remained high for at least 7 days, reaching the peak at 7 days, M2 microglia gradually increased after 3 days and continued to increase for at least 14 days. Furthermore, PCE inhibited the secretion of pro-inflammatory cytokines in M1 microglia and improved the secretion of anti-inflammatory cytokines in M2 microglia, which related to the regulation of the IRF5-IRF4 axis. This current study indicates that PCE alleviates tPA-induced HT after ischemic stroke by modulating microglia M1/M2 phenotype polarization.

Spontaneous bleeding in chronic kidney disease: global coagulation assays may predict bleeding risk.

Background: Chronic kidney disease (CKD) is associated with increased bleeding and thrombotic risks. Standard blood tests do not sufficiently quantify these risks. Global coagulation assays (GCAs) provide a more comprehensive assessment of coagulation. Objectives: We aimed to evaluate if GCAs are predictive of spontaneous major bleeding (sMB) in CKD. Methods: Adult patients with CKD (estimated glomerular filtration rate, <30 mL/min/1.73m2) were recruited to this pilot prospective observational study. Testing with GCAs (thromboelastography, overall hemostatic potential, calibrated automated thrombogram, and plasminogen activator inhibitor-1) was performed, and the results were correlated to sMB events. Results: Eighty-seven CKD patients (median age, 67 years; 67.8% male) were included, with median follow-up of 3.1 years. CKD patients demonstrated elevated fibrinogen, factor VIII, and von Willebrand factor antigen levels, while other conventional coagulation test results were within reference intervals. Ten episodes of sMB (11.5%) were captured (3.0/100 person-years), with no significant association demonstrated between sMB and antiplatelet use (P = .36), platelet count (P = .14), or renal function (urea, P = .27; estimated glomerular filtration rate, P = .09). CKD patients with sMB had more hypocoagulable GCA parameters compared with those without sMB. The lowest quartiles of endogenous thrombin potential (subhazard ratio [sHR], 7.11; 95% CI, 1.84-27.45), overall hemostatic potential (sHR, 6.81; 95% CI, 1.77-26.16), and plasminogen activator inhibitor-1 (sHR, 5.26; 95% CI, 1.55-17.91) were associated with sMB. Conclusion: This pilot study demonstrates that GCAs such as thrombin and fibrin generation may predict sMB risk in patients with CKD, which has potential to be practice-changing. Larger studies are required to validate these findings.

Endothelial Dysfunction in Obesity and Therapeutic Targets.

Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter ß, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.

Successful Treatment of Central Retinal Artery Occlusion With Tissue Plasminogen Activator Followed by Recurrent Retinal Ischemia.

Purpose: To describe the use of intra-arterial tissue plasminogen activator (tPA) to treat central retinal artery occlusion (CRAO). Methods: A case and its findings were analyzed. Results: A 45-year-old man diagnosed with a CRAO and had cerebral angiography and treatment with intra-arterial tPA. After treatment, follow-up included optical coherence tomography (OCT), fundus photography, fluorescein angiography, and OCT angiography. The visual acuity (VA) improved from hand motions to 20/30 immediately after fibrinolysis. A vascular occlusion event the next day resulted in a decrease in VA to 20/400. After initiation of dual antiplatelet therapy, the patient's VA improved to 20/20. As the retina recovered, the evolution of retinal ischemic changes to a finding similar to paracentral acute middle maculopathy was seen on imaging. Conclusions: This is the first report describing a patient safely started on dual antiplatelet therapy that led to vision improvement after initial treatment with intra-arterial tPA for a CRAO resulted in recurrent vision loss.

Novel Biomarkers: Soluble Urokinase-Type Plasminogen Activator Receptor and Procalcitonin- and Histological Chorioamnionitis after Preterm Premature Rupture of Membranes.

Fetal inflammatory response syndrome or infection after preterm premature rupture of membranes (PPROM) increases neonatal morbidity in preterm deliveries. Biochemical markers from the amniotic fluid (AF) have been used to evaluate possible intra-amniotic infection during the asymptomatic phase after PPROM. This study aimed to describe whether soluble urokinase-type plasminogen activator receptor (suPAR) or procalcitonin (PCT) from AF or maternal sera could reveal fetal inflammatory response or infection after PPROM. AF and maternal serum samples were collected weekly after PPROM (23+ 0 - 34+ 6 gestational weeks) until delivery from twenty women and two women with possible chorioamnionitis with intact membranes. Levels of suPAR, PCT, interleukin-6 (IL-6), glucose, lactate dehydrogenase (LDH), and bacterial PCR were determined from AF and suPAR and PCT and IL-6 from maternal sera. Fetal infection or inflammation response were determined by the histology of the placenta after delivery. AF glucose was significantly lower and AF LDH higher in the fetal site histologic chorioamnionitis (HCA) group, while AF suPAR concentrations tended to be higher in this group. AF suPAR correlated significantly with AF glucose and LDH. Based on receiver operating characteristic (ROC) analysis, AF glucose had the best predictability for fetal site histological chorioamnionitis. The findings of AF PCT were insignificant considering HCA. AF glucose had the highest accuracy in predicting fetal site histologic chorioamnionitis. AF suPAR may be a promising marker; however, our findings were limited by a small study population.

Targeting Fibrinolytic Inhibition for Venous Thromboembolism Treatment: Overview of an Emerging Therapeutic Approach.

Venous thrombosis and pulmonary embolism (venous thromboembolism) are important causes of morbidity and mortality worldwide. In patients with venous thromboembolism, thrombi obstruct blood vessels and resist physiological dissolution (fibrinolysis), which can be life threatening and cause chronic complications. Plasminogen activator therapy, which was developed >50 years ago, is effective in dissolving thrombi but has unacceptable bleeding risks. Safe dissolution of thrombi in patients with venous thromboembolism has been elusive despite multiple innovations in plasminogen activator design and catheter-based therapy. Evidence now suggests that fibrinolysis is rigidly controlled by endogenous fibrinolysis inhibitors, including α2-antiplasmin, plasminogen activator inhibitor-1, and thrombin-activable fibrinolysis inhibitor. Elevated levels of these fibrinolysis inhibitors are associated with an increased risk of venous thromboembolism in humans. New therapeutic paradigms suggest that accelerated and effective fibrinolysis may be achieved safely by therapeutically targeting these fibrinolytic inhibitors in venous thromboembolism. In this article, we discuss the role of fibrinolytic components in venous thromboembolism and the current status of research and development targeting fibrinolysis inhibitors.

Pharmacokinetics and pharmacodynamics of low doses of recombinant tissue plasminogen activator to establish a model for biosimilarity comparisons.

Background: Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent and essential in emergency medical care. Given recent supply shortages, the availability of biosimilar products is an urgent medical need. However, biosimilarity trials are difficult to perform in critically ill patients. Objectives: The aim of this pilot study was to investigate the pharmacokinetics and pharmacodynamics of low rt-PA doses to establish a model for testing proposed biosimilars in healthy volunteers. Methods: Eight healthy volunteers received 0.02 to 0.05 mg/kg rt-PA on 3 study days; blood samples were obtained every 4 minutes after the end of the bolus infusion to measure rt-PA antigen levels by enzyme immunoassay, and the pharmacodynamics were assessed with rotational thromboelastometry. Results: Bolus infusion of low rt-PA doses was safe and well tolerated. Maximal plasma concentrations and the area under the curve increased dose-dependently. Time-concentration curves were clearly separated between the lower and the higher doses. As expected, the half-live of rt-PA was short (4.5-5 min), and representative for therapeutic doses. The intrasubject coefficient variations were moderate (<25%). Bolus infusion of rt-PA dose-dependently shortened lysis time and lysis onset time in both dose groups and caused maximum clot lysis of 100% in all participants. Conclusion: In conclusion, the pharmacokinetics of rt-PA was dose linear and displayed limited intrasubject variability even at subtherapeutic doses. The half-life and thus clearance of rt-PA was representative of full therapeutic doses. The lysis time was shortened in a dose and time-dependent fashion and was clearly distinguishable between doses. Thus, the model appears to be suitable and sensitive to test biosimilarity.

Assessing mortality and safety of IV thrombolysis in ischemic stroke patients on direct oral anticoagulants (DOACs): A systematic review and meta-analysis.

BACKGROUND: Intravenous thrombolysis (IVT) is considered a standard reperfusion therapy for acute ischemic stroke (AIS) patients presenting within 4.5 hours of the last known well (LKW). Current guidelines contraindicate the use of IVT in patients within the window who are on Direct Oral Anticoagulants (DOACs) and took their last dose within 48 hours of presentation, due to a risk of symptomatic intracranial hemorrhage (sICH). OBJECTIVE: To assess the safety of IVT as management of AIS in patients who take DOACs. METHODS: A thorough literature search of four databases (PubMed, Scopus, Medline, Google Scholar, Web of science and ScienceDirect) was done from inception until May 2023. Double-arm studies that reported outcomes of mortality, sICH, and mRS scores were selected. Results from these studies were presented as odds ratios (ORs) with 95 % confidence intervals (CIs) and were pooled using a random-effects model. RESULTS: Four eligible studies were included with a total of 238,425 stroke patients who underwent IVT (3330 in the DOAC arm and 235,217 in the placebo arm). The group with prior DOAC intake showed a significant decrease in sICH development and an increase in functional independence at 90 days compared to the control group. No significant association was seen between prior DOAC use and any serious alteplase-related complication within 36 hours, serious systemic or life-threatening hemorrhage within 36 hours, mortality within 3 months, or mRS score at 3 months. CONCLUSION: The pooled analysis suggests that IVT is a safe management option for acute ischemic stroke in patients with DOAC intake before symptom onset without an increased risk of serious adverse events.

Inter-Organ Communication Involved in Brown Adipose Tissue Thermogenesis.

Brown and beige adipocytes produce heat from substrates such as fatty acids and glucose. Such heat productions occur in response to various stimuli and are called adaptive non-shivering thermogenesis. This review introduces mechanisms known to regulate brown and beige adipocyte thermogenesis. Leptin and fibroblast growth factor 21 (FGF21) are examples of periphery-derived humoral factors that act on the central nervous system (CNS) and increase brown adipose tissue (BAT) thermogenesis. Additionally, neuronal signals such as those induced by intestinal cholecystokinin and hepatic peroxisome proliferator-activated receptor γ travel through vagal afferent-CNS-sympathetic efferent-BAT pathways and increase BAT thermogenesis. By contrast, some periphery-derived humoral factors (ghrelin, adiponectin, plasminogen activator inhibitor-1, and soluble leptin receptor) act also on CNS but inhibit BAT thermogenesis. Neuronal signals also reduce BAT sympathetic activities and BAT thermogenesis, one such example being signals derived by hepatic glucokinase activation. Beige adipocytes can be induced by myokines (interleukin 6, irisin, and ß-aminoisobutyric acid), hepatokines (FGF21), and cardiac-secreted factors (brain natriuretic peptide). Cold temperature and leptin also stimulate beige adipocytes via sympathetic activation. Further investigation on inter-organ communication involving adipocyte thermogenesis may lead to the elucidation of how body temperature is regulated and, moreover, to the development of novel strategies to treat metabolic disorders.

Effects of intracameral tissue plasminogen activator injection on posterior capsular opacification, fibrin formation, and intraocular pressure in dogs after phacoemulsification.

OBJECTIVE: To evaluate whether intracameral tissue plasminogen activator (tPA) injection is effective in regulating posterior capsular opacification (PCO), fibrin formation and intraocular pressure (IOP) after cataract surgery. ANIMAL STUDIED: Prospective study involving 30 eyes of 21 dogs that underwent phacoemulsification. PROCEDURES: Thirty eyes were randomly divided into two groups of 15 eyes (control and tPA groups). Intracameral tPA (25 µg/0.1 mL) was injected into tPA group eyes before corneal incision closure but not into the eyes of the control group. The grades of anterior fibrin formation and PCO were compared based on slit lamp biomicroscope examination at 1 and 2 weeks, 1 month, and 2-3 months postoperatively. IOP was measured using applanation tonometry every 30 min for 4 h immediately after operation and on the following morning. The IOP of the two groups at each time was compared. RESULTS: The grade of anterior fibrin formation and that of PCO were not significantly different between the two groups at any time point (p > .05). However, the IOP of the tPA group was significantly lower than that of the control group at each point on the day of surgery (p < .05). No complications were observed with tPA injection, except for temporary hyphema (for 3 days) in one eye. CONCLUSIONS: Although the intracameral tPA injection did not affect anterior fibrin formation and PCO, it effectively maintained normal IOP immediately after phacoemulsification. Thus, our findings provide valuable insights into the potential benefits of intracameral tPA injection in achieving immediate IOP control after phacoemulsification.