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Item Contribution of fibrinolysis to the physical component summary of the SF-36 after acute submassive pulmonary embolism(Springer US, 2015-08) Stewart, Lauren K.; Peitz, Geoffrey W.; Nordenholz, Kristen E.; Courtney, D. Mark; Kabrhel, Christopher; Jones, Alan E.; Rondina, Matthew T.; Diercks, Deborah B.; Klinger, James R.; Kline, Jeffrey A.; Department of Emergency Medicine, School of MedicineAcute pulmonary embolism (PE) can diminish patient quality of life (QoL). The objective was to test whether treatment with tenecteplase has an independent effect on a measurement that reflects QoL in patients with submassive PE. This was a secondary analysis of an 8-center, prospective randomized controlled trial, utilizing multivariate regression to control for predefined predictors of worsened QoL including: age, active malignancy, history of PE or deep venous thrombosis (DVT), recurrent PE or DVT, chronic obstructive pulmonary disease and heart failure. QoL was measured with the physical component summary (PCS) of the SF-36. Analysis included 76 patients (37 randomized to tenecteplase, 39 to placebo). Multivariate regression yielded an equation f(8, 67), P<0.001, with R2 = 0.303. Obesity had the largest effect on PCS (β = −8.6, P<0.001), with tenecteplase second (β = 4.73, P = 0.056). After controlling for all interactions, tenecteplase increased the PCS by +5.37 points (P = 0.027). In patients without any of the defined comorbidities, the coefficient on the tenecteplase variable was not significant (−0.835, P = 0.777). In patients with submassive PE, obesity had the greatest influence on QoL, followed by use of fibrinolysis. Fibrinolysis had a marginal independent effect on patient QoL after controlling for comorbidities, but was not significant in patients without comorbid conditions.Item Current Management of Acute Pulmonary Embolism(AME Publishing Company, 2020) Martinez Licha, Carlos R.; McCurdy, Chelsea M.; Maldonado, Sarina Masso; Lee, Lawrence S.; Medicine, School of MedicinePurpose: Acute pulmonary embolism (PE) remains a significant cause of morbidity and requires prompt diagnosis and management. While non-surgical approaches have supplanted surgery as primary treatment, surgical pulmonary embolectomy (SPE) remains a vital option for select patients. We review the current management of acute PE, with a focus on surgical therapy. Methods: A PubMed search was performed to identify literature regarding PE and treatment. Results were filtered to include the most comprehensive publications over the past decade. Results: PE is stratified based on presenting hemodynamic status or degree of mechanical pulmonary arterial occlusion. Although systemic or catheter-guided fibrinolysis is the preferred first-line treatment for the majority of cases, patients who are not candidates should be considered for SPE. Studies demonstrate no mortality benefit of thrombolysis over surgery. Systemic anticoagulation is a mainstay of treatment regardless of intervention approach. Following surgical embolectomy, direct oral anticoagulants (DOACs) have been shown to reduce recurrence of thromboembolism. Conclusions: Acute PE presents with varying degrees of clinical stability. Patients should be evaluated in the context of various available treatment options including medical, catheter-based, and surgical interventions. SPE is a safe and appropriate treatment option for appropriate patients.Item Differential effect of mild and severe pulmonary embolism on the rat lung transcriptome(Springer (Biomed Central Ltd.), 2016-07-19) Zagorski, John; Kline, Jeffrey A.; Department of Emergency Medicine, IU School of MedicineBACKGROUND: Pulmonary thromboembolism (PTE) is a common diagnosis and a leading cause of cardiovascular morbidity and mortality. A growing literature has associated PE with systemic inflammation, and global hyper-coagulability, which contribute to lung remodeling and clot recurrence. The source and mechanism of inflammation remains unstudied. In humans, inhibition of cholesterol synthesis with statins decreases biomarkers of inflammation. We test the differential effect of pulmonary vascular occlusion during mild and severe pulmonary embolism on the lung transcriptome. METHODS: Experimental PE was induced in adult male rats by injection of 25 micron polystyrene microspheres into the jugular vein. The effect of Mild PE, (2-h right ventricular systolic pressure [RVSP] normal, 18-h RVSP 44 mmHg) and Severe PE (2-h RVSP > 50 mmHg; 18-h RVSP 44 mmHg) on lungs was assessed by measuring transcriptome-wide changes in gene expression by DNA microarrays. RESULTS: Severe PE was associated with a large change in lung gene expression and in the expression of KEGG pathways and other gene functional annotation groups. Mild PE was also associated with a large number of significant changes in gene expression and in the expression of KEGG pathways and gene functional annotation groups, even after only 2 h of PE. Up-regulated pathways included increased adipocytokine, chemokine and cytokine signaling as well as cholesterol synthesis. CONCLUSIONS: Mild PE without acute pulmonary hypertension (PH) increased lung gene expression of inflammatory pathways, including increased cholesterol synthesis. These data indicate that even mild persistent pulmonary vascular occlusion is capable of inciting an inflammatory response from the lung. These data imply the detrimental effect of unresolved pulmonary obstruction from PE.Item Leukocyte Expression of Heme Oxygenase-1 [hmox1] Varies Inversely with Severity of Tricuspid Regurgitation in Acute Pulmonary Embolism.(Elsevier, 2015-10) Kline, Jeffrey A.; Steuerwald, Nury M.; Watts, John A.; Courtney, Mark; Bonkovsky, Herbert L.; Department of Emergency Medicine, IU School of MedicineObjective: Pulmonary embolism (PE) can cause intracardiac hemolysis and increased plasma hemoglobin and arginase-1, which can worsen pulmonary vasoconstriction. We test the hypothesis that patients with PE that causes tricuspid regurgitation (TR), indicative of higher pulmonary arterial pressures, have decreased leukocyte expression of hmox-1 compared with patients with PE and no TR and patients without PE. Design: Prospective, noninterventional study. Patients: Normotensive patients with suspected PE (n=87) who underwent CT pulmonary angiography and transthoracic Doppler-echocardiography. Measurements: Significant TR was defined as a jet velocity > 2.7m/s. Leukocyte expression of hmox-1, haptoglobin, haptoglobin related gene, the haptoglobin receptor, CD163 and cox-2 genes were assessed by quantitative rtPCR, and the hmox-1 promoter was examined for the −413 A→T SNP and GT repeat polymorphisms. Results: Of the 44 (50%) with PE+, 22 had TR+, and their mean pulmonary vascular occlusion (39±32%) did not differ significantly from patients who were TR− (28±26%, P=0.15). Patients with PE+ and TR+ had significantly lower expression of hmox-1 and haptoglobin genes than patients without PE+ and no TR. Expression of hmox-1 varied inversely with TR velocity (r2=0.45, P<0.001) for PE+ (n=22) but not patients without PE. Hmox-1 expression did not vary significantly with genotype. Cox-2 did not differ between groups and had no correlation with TR. Conclusions: Severity of TR varied inversely with hmox-1 expression, suggesting that hmox-1 expression affects pulmonary vascular reactivity after PE.Item Real-time tracking of fibrinolysis under constant wall shear and various pulsatile flows in an in-vitro thrombolysis model(Wiley, 2023-04-11) Zeng, Ziqian; Christodoulides, Alexei; Alves, Nathan J.; Emergency Medicine, School of MedicineA great need exists for the development of a more representative in‐vitro model to efficiently screen novel thrombolytic therapies. We herein report the design, validation, and characterization of a highly reproducible, physiological scale, flowing clot lysis platform with real‐time fibrinolysis monitoring to screen thrombolytic drugs utilizing a fluorescein isothiocyanate (FITC)‐labeled clot analog. Using this Real‐Time Fluorometric Flowing Fibrinolysis assay (RT‐FluFF assay), a tPa‐dependent degree of thrombolysis was observed both via clot mass loss as well as fluorometrically monitored release of FITC‐labeled fibrin degradation products. Percent clot mass loss ranged from 33.6% to 85.9% with fluorescence release rates of 0.53 to 1.17 RFU/min in 40 and 1000 ng/mL tPa conditions, respectively. The platform is easily adapted to produce pulsatile flows. Hemodynamics of human main pulmonary artery were mimicked through matching dimensionless flow parameters calculated using clinical data. Increasing pressure amplitude range (4–40 mmHg) results in a 20% increase of fibrinolysis at 1000 ng/mL tPA. Increasing shear flow rate (205–913 s−1) significantly increases fibrinolysis and mechanical digestion. These findings suggest pulsatile level affects thrombolytic drug activities and the proposed in‐vitro clot model offers a versatile testing platform for thrombolytic drug screening.Item Role of coagulation in persistent renal ischemia following reperfusion in an animal model(American Physiological Society, 2022) Dominguez, Jesus H.; Xie, Danhui; Dominguez, James M., II; Kelly, K. J.; Medicine, School of MedicineIschemic acute kidney injury is common, deadly, and accelerates the progression of chronic kidney disease, yet has no specific therapy. After ischemia, reperfusion is patchy with early and persistent impairment in regional renal blood flow and cellular injury. We tested the hypothesis that intrarenal coagulation results in sustained renal ischemia following reperfusion, using a well-characterized model. Markedly decreased, but heterogeneous, microvascular plasma flow with microthrombi was found postischemia by intravital microscopy. Widespread tissue factor expression and fibrin deposition were also apparent. Clotting was accompanied by complement activation and inflammation. Treatment with exosomes derived from renal tubular cells or with the fibrinolytic urokinase, given 24 h postischemia when renal failure was established, significantly improved microvascular flow, coagulation, serum creatinine, and histological evidence of injury. These data support the hypothesis that intrarenal clotting occurs early and the resultant sustained ischemia is a critical determinant of renal failure following ischemia; they demonstrate that the coagulation abnormalities are amenable to therapy and that therapy results in improvement in both function and postischemic inflammation. NEW & NOTEWORTHY: Ischemic renal injury carries very high morbidity and mortality, yet has no specific therapy. We found markedly decreased, heterogeneous microvascular plasma flow, tissue factor induction, fibrin deposition, and microthrombi after renal ischemia-reperfusion using a well-characterized model. Renal exosomes or the fibrinolytic urokinase, administered after renal failure was established, improved microvascular flow, coagulation, renal function, and histology. Data demonstrate that intrarenal clotting results in sustained ischemia amenable to therapy that improves both function and postischemic inflammation.Item Variable Resistance to Plasminogen Activator Initiated Fibrinolysis for Intermediate-Risk Pulmonary Embolism.(PLOS, 2016) Stubblefield, William B.; Alves, Nathan J.; Rondina, Matthew T.; Kline, Jeffrey A.; Department of Emergency Medicine, IU School of MedicineBackground: We examine the clinical significance and biomarkers of tissue plasminogen activator (tPA)-catalyzed clot lysis time (CLT) in patients with intermediate-risk pulmonary embolism (PE). Methods: Platelet-poor, citrated plasma was obtained from patients with PE. Healthy age- and sex-matched patients served as disease-negative controls. Fibrinogen, α2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen activator Inhibitor 1 (PAI-1), thrombin time and D-dimer were quantified. Clotting was induced using CaCl2, tissue factor, and phospholipid. Lysis was induced using 60 ng/mL tPA. Time to 50% clot lysis (CLT) was assessed by both thromboelastography (TEG) and turbidimetry (A405). Results: Compared with disease-negative controls, patients with PE exhibited significantly longer mean CLT on TEG (+2,580 seconds, 95% CI 1,380 to 3,720 sec). Patients with PE and a short CLT who were treated with tenecteplase had increased risk of bleeding, whereas those with long CLT had significantly worse exercise tolerance and psychometric testing for quality of life at 3 months. A multivariate stepwise removal regression model selected PAI-1 and TAFI as predictive biomarkers of CLT. Conclusion: The CLT from TEG predicted increased risk of bleeding and clinical failure with tenecteplase treatment for intermediate-risk PE. Plasmatic PAI-1 and TAFI were independent predictors of CLT.Item Viscoelastic Testing and Coagulopathy of Traumatic Brain Injury(MDPI, 2021-10-28) Bradbury, Jamie L.; Thomas, Scott G.; Sorg, Nikki R.; Mjaess, Nicolas; Berquist, Margaret R.; Brenner, Toby J.; Langford, Jack H.; Marsee, Mathew K.; Moody, Ashton N.; Bunch, Connor M.; Sing, Sandeep R.; Al-Fadhl, Mahmoud D.; Salamah, Qussai; Saleh, Tarek; Patel, Neal B.; Shaikh, Kashif A.; Smith, Stephen M.; Langheinrich, Walter S.; Fulkerson, Daniel H.; Sixta, Sherry; Neurological Surgery, School of MedicineA unique coagulopathy often manifests following traumatic brain injury, leading the clinician down a difficult decision path on appropriate prophylaxis and therapy. Conventional coagulation assays—such as prothrombin time, partial thromboplastin time, and international normalized ratio—have historically been utilized to assess hemostasis and guide treatment following traumatic brain injury. However, these plasma-based assays alone often lack the sensitivity to diagnose and adequately treat coagulopathy associated with traumatic brain injury. Here, we review the whole blood coagulation assays termed viscoelastic tests and their use in traumatic brain injury. Modified viscoelastic tests with platelet function assays have helped elucidate the underlying pathophysiology and guide clinical decisions in a goal-directed fashion. Platelet dysfunction appears to underlie most coagulopathies in this patient population, particularly at the adenosine diphosphate and/or arachidonic acid receptors. Future research will focus not only on the utility of viscoelastic tests in diagnosing coagulopathy in traumatic brain injury, but also on better defining the use of these tests as evidence-based and/or precision-based tools to improve patient outcomes.