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Eugene Braunwald - One of the best experts on this subject based on the ideXlab platform.

Elliott M Antman - One of the best experts on this subject based on the ideXlab platform.

  • Fibrinolysis use among patients requiring interhospital transfer for st segment elevation myocardial infarction care a report from the us national cardiovascular data registry
    JAMA Internal Medicine, 2015
    Co-Authors: Amit N Vora, Dajuanicia N Holmes, Ivan C Rokos, Matthew T Roe, Christopher B Granger, William J French, Elliott M Antman, Timothy D Henry, Laine Thomas, Eric R Bates
    Abstract:

    Importance Guidelines for patients with ST-segment elevation myocardial infarction (STEMI) recommend timely reperfusion with primary percutaneous coronary intervention (pPCI) or Fibrinolysis. Among patients with STEMI who require interhospital transfer, it is unclear how reperfusion strategy selection and outcomes vary with interhospital drive times. Objective To assess the association of estimated interhospital drive times with reperfusion strategy selection among transferred patients with STEMI in the United States. Design, Setting, and Participants We identified 22 481 patients eligible for pPCI or Fibrinolysis who were transferred from 1771 STEMI referring centers to 366 STEMI receiving centers in the Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines database between July 1, 2008, and March 31, 2012. Main Outcomes and Measures In-hospital mortality and major bleeding. Results The median estimated interhospital drive time was 57 minutes (interquartile range [IQR], 36-88 minutes). When the estimated drive time exceeded 30 minutes, only 42.6% of transfer patients treated with pPCI achieved the first door-to-balloon time within 120 minutes. Only 52.7% of eligible patients with a drive time exceeding 60 minutes received Fibrinolysis. Among 15 437 patients with estimated drive times of 30 to 120 minutes who were eligible for Fibrinolysis or pPCI, 5296 (34.3%) received pretransfer Fibrinolysis, with a median door-to-needle time of 34 minutes (IQR, 23-53 minutes). After Fibrinolysis, the median time to transfer to the STEMI receiving center was 49 minutes (IQR, 34-69 minutes), and 97.1% underwent follow-up angiography. Patients treated with Fibrinolysis vs pPCI had no significant mortality difference (3.7% vs 3.9%; adjusted odds ratio, 1.13; 95% CI, 0.94-1.36) but had higher bleeding risk (10.7% vs 9.5%; adjusted odds ratio, 1.17; 95% CI, 1.02-1.33). Conclusions and Relevance In the United States, neither Fibrinolysis nor pPCI is being optimally used to achieve guideline-recommended reperfusion targets. For patients who are unlikely to receive timely pPCI, pretransfer Fibrinolysis, followed by early transfer for angiography, may be a reperfusion option when potential benefits of timely reperfusion outweigh bleeding risk.

  • poor outcomes after fibrinolytic therapy for st segment elevation myocardial infarction impact of age a meta analysis of a decade of trials
    Journal of Thrombosis and Thrombolysis, 2006
    Co-Authors: Shaheeda Ahmed, Elliott M Antman, Sabina A Murphy, Robert P Giugliano, Christopher P Cannon, Harvey D White, David A Morrow, Eugene Braunwald
    Abstract:

    Background: Fibrinolysis for ST-segment elevation myocardial infarction (STEMI) reduces mortality, but its relative efficacy and risks are age-dependent. We aimed to quantify the outcomes of Fibrinolysis and adjunctive antithrombin therapy for STEMI stratified by age.

Laszlo Bajzar - One of the best experts on this subject based on the ideXlab platform.

  • Thrombin activatable Fibrinolysis inhibitor : not just an inhibitor of Fibrinolysis
    Critical Care Medicine, 2004
    Co-Authors: Laszlo Bajzar, Nidhi Jain, Ping Wang, John Walker
    Abstract:

    Objective: To review the activation of thrombin activatable Fibrinolysis inhibitor (TAFI) and activity of activated TAFI (TAFIa) as it relates to the regulation of both fibrinolytic and proinflammatory substances. Data Source: Published articles and reviews (from PubMed, published between 1962 and 2003) on experimental studies of coagulation, Fibrinolysis, and inflammation. Data Synthesis and Conclusions: The principal physiologic role of TAFI is still a matter of debate. Although TAFI activation can result from proteolysis by a number of proteases, the most likely physiologic activators are thrombin (in complex with the cofactor thrombomodulin) and plasmin (in complex with polysaccharide cofactors). The activated enzyme, TAFIa, displays carboxypeptidase B-like activity and probably regulates both Fibrinolysis and inflammation in response to injury and infection. At present, there is limited understanding of the role that TAFI plays in the interrelationships between coagulation, Fibrinolysis, and inflammation. Although the potential therapeutic value of TAFIa inhibition/TAFI activation awaits further investigation, the data gathered to date suggest that, like activated protein C, TAFIa may play a pivotal role in regulating the crosstalk between coagulation, Fibrinolysis, and inflammation.

  • Thrombin activatable Fibrinolysis inhibitor: not just an inhibitor of Fibrinolysis.
    Critical care medicine, 2004
    Co-Authors: Laszlo Bajzar, Nidhi Jain, Ping Wang, John B Walker
    Abstract:

    To review the activation of thrombin activatable Fibrinolysis inhibitor (TAFI) and activity of activated TAFI (TAFIa) as it relates to the regulation of both fibrinolytic and proinflammatory substances. Published articles and reviews (from PubMed, published between 1962 and 2003) on experimental studies of coagulation, Fibrinolysis, and inflammation. The principal physiologic role of TAFI is still a matter of debate. Although TAFI activation can result from proteolysis by a number of proteases, the most likely physiologic activators are thrombin (in complex with the cofactor thrombomodulin) and plasmin (in complex with polysaccharide cofactors). The activated enzyme, TAFIa, displays carboxypeptidase B-like activity and probably regulates both Fibrinolysis and inflammation in response to injury and infection. At present, there is limited understanding of the role that TAFI plays in the interrelationships between coagulation, Fibrinolysis, and inflammation. Although the potential therapeutic value of TAFIa inhibition/TAFI activation awaits further investigation, the data gathered to date suggest that, like activated protein C, TAFIa may play a pivotal role in regulating the crosstalk between coagulation, Fibrinolysis, and inflammation.

  • A Study of the Mechanism of Inhibition of Fibrinolysis by Activated Thrombin-activable Fibrinolysis Inhibitor
    Journal of Biological Chemistry, 1998
    Co-Authors: Wei Wang, Michael B. Boffa, Laszlo Bajzar, John Walker, Michael E. Nesheim
    Abstract:

    Abstract TAFI (thrombin-activable Fibrinolysis inhibitor) is a recently described plasma zymogen that, when exposed to the thrombin-thrombomodulin complex, is converted by proteolysis at Arg92 to a basic carboxypeptidase that inhibits Fibrinolysis (TAFIa). The studies described here were undertaken to elucidate the molecular basis for the inhibition of Fibrinolysis. When TAFIa is included in a clot undergoing Fibrinolysis induced by tissue plasminogen activator and plasminogen, the time to achieve lysis is prolonged, and free arginine and lysine are released over time. In addition, TAFIa prevents a 2.5-fold increase in the rate constant for plasminogen activation which occurs when fibrin is modified by plasmin in the early course of fibrin degradation. The effect is specific for the Glu- form of plasminogen. TAFIa prevents or at least attenuates positive feedback expressed through Lys-plasminogen formation during the process of Fibrinolysis initiated by tissue plasminogen activator and plasminogen. TAFIa also inhibits plasmin activity in a clot and prolongs Fibrinolysis initiated with plasmin. We conclude that TAFIa suppresses Fibrinolysis by removing COOH-terminal lysine and arginine residues from fibrin, thereby reducing its cofactor functions in both plasminogen activation and the positive feedback conversion of Glu-plasminogen to Lys-plasminogen. At relatively elevated concentrations, it also directly inhibits plasmin.

  • thrombin thrombomodulin and tafi in the molecular link between coagulation and Fibrinolysis
    Thrombosis and Haemostasis, 1997
    Co-Authors: Michael E. Nesheim, Wei Wang, Michael B. Boffa, Mariko Nagashima, John Morser, Laszlo Bajzar
    Abstract:

    Abstract The thrombin thrombomodulin dependent activation of the plasma protein TAFI (Thrombin Activatable Fibrinolysis Inhibitor) and Subsequent Inhibition of Fibrinolysis by the TAFIa is described. Work to date indicates that TAFIa is a carboxypeptidase B enzyme that suppress Fibrinolysis most likely by down regulating the cofactor functions of partially degraded fibrin. The existence of TAFI provides the explanation for the apparent profibrinolytic effect of activated protein C. and implies the existence of an explicit molecular connection between the blood coagulation of fibrinolytic cascades that is expressed through the thrombin thrombomodulin dependent activation of TAFI. Thus, thrombin generation can, in principle, result in the suppression of Fibrinolysis.

Biykem Bozkurt - One of the best experts on this subject based on the ideXlab platform.

  • temporal trends in care and outcomes of patients receiving fibrinolytic therapy compared to primary percutaneous coronary intervention insights from the get with the guidelines coronary artery disease gwtg cad registry
    Journal of the American Heart Association, 2016
    Co-Authors: Rajiv S. Hira, Christine Ju, Paul A Heidenreich, Biykem Bozkurt, Salim S Virani, Deepak L Bhatt, Gregg C Fonarow
    Abstract:

    Background Timely reperfusion after ST‐elevation myocardial infarction (STEMI) improves survival. Guidelines recommend primary percutaneous coronary intervention (PPCI) within 90 minutes of arrival at a PCI‐capable hospital. The alternative is Fibrinolysis within 30 minutes for those in those for whom timely transfer to a PCI‐capable hospital is not feasible. Methods and Results We identified STEMI patients receiving reperfusion therapy at 229 hospitals participating in the Get With the Guidelines—Coronary Artery Disease (GWTG‐CAD) database (January 1, 2003 through December 31, 2008). Temporal trends in the use of Fibrinolysis and PPCI, its timeliness, and in‐hospital mortality outcomes were assessed. We also assessed predictors of Fibrinolysis versus PPCI and compliance with performance measures. Defect‐free care was defined as 100% compliance with all performance measures. We identified 29 190 STEMI patients, of whom 2441 (8.4%) received Fibrinolysis; 38.2% of these patients achieved door‐to‐needle times ≤30 minutes. Median door‐to‐needle times increased from 36 to 60 minutes ( P =0.005) over the study period. Among PPCI patients, median door‐to‐balloon times decreased from 94 to 64 minutes ( P <0.0001) over the same period. In‐hospital mortality was higher with Fibrinolysis than with PPCI (4.6% vs 3.3%, P =0.001) and did not change significantly over time. Patients receiving Fibrinolysis were less likely to receive defect‐free care compared with their PPCI counterparts. Conclusions Use of Fibrinolysis for STEMI has decreased over time with concomitant worsening of door‐to‐needle times. Over the same time period, use of PPCI increased with improvement in door‐to‐balloon times. In‐hospital mortality was higher with Fibrinolysis than with PPCI. As reperfusion for STEMI continues to shift from Fibrinolysis to PPCI, it will be critical to ensure that door‐to‐needle times and outcomes do not worsen.

  • temporal trends in care and outcomes of patients receiving fibrinolytic therapy compared to primary percutaneous coronary intervention insights from the get with the guidelines coronary artery disease gwtg cad registry
    Journal of the American Heart Association, 2016
    Co-Authors: Rajiv S. Hira, Christine Ju, Paul A Heidenreich, Biykem Bozkurt, Salim S Virani, Deepak L Bhatt, Gregg C Fonarow
    Abstract:

    Background Timely reperfusion after ST‐elevation myocardial infarction (STEMI) improves survival. Guidelines recommend primary percutaneous coronary intervention (PPCI) within 90 minutes of arrival at a PCI‐capable hospital. The alternative is Fibrinolysis within 30 minutes for those in those for whom timely transfer to a PCI‐capable hospital is not feasible. Methods and Results We identified STEMI patients receiving reperfusion therapy at 229 hospitals participating in the Get With the Guidelines—Coronary Artery Disease (GWTG‐CAD) database (January 1, 2003 through December 31, 2008). Temporal trends in the use of Fibrinolysis and PPCI, its timeliness, and in‐hospital mortality outcomes were assessed. We also assessed predictors of Fibrinolysis versus PPCI and compliance with performance measures. Defect‐free care was defined as 100% compliance with all performance measures. We identified 29 190 STEMI patients, of whom 2441 (8.4%) received Fibrinolysis; 38.2% of these patients achieved door‐to‐needle times ≤30 minutes. Median door‐to‐needle times increased from 36 to 60 minutes ( P =0.005) over the study period. Among PPCI patients, median door‐to‐balloon times decreased from 94 to 64 minutes ( P <0.0001) over the same period. In‐hospital mortality was higher with Fibrinolysis than with PPCI (4.6% vs 3.3%, P =0.001) and did not change significantly over time. Patients receiving Fibrinolysis were less likely to receive defect‐free care compared with their PPCI counterparts. Conclusions Use of Fibrinolysis for STEMI has decreased over time with concomitant worsening of door‐to‐needle times. Over the same time period, use of PPCI increased with improvement in door‐to‐balloon times. In‐hospital mortality was higher with Fibrinolysis than with PPCI. As reperfusion for STEMI continues to shift from Fibrinolysis to PPCI, it will be critical to ensure that door‐to‐needle times and outcomes do not worsen.

Ernest E Moore - One of the best experts on this subject based on the ideXlab platform.

  • Do not drink and lyse: alcohol intoxication increases Fibrinolysis shutdown in injured patients
    European Journal of Trauma and Emergency Surgery, 2020
    Co-Authors: Gregory R. Stettler, Geoffrey R. Nunns, Hunter B. Moore, Benjamin R. Huebner, Anirban Banerjee, Christopher C. Silliman, Ernest E Moore, Angela Sauaia
    Abstract:

    Introduction High alcohol consumption has been associated with decreased Fibrinolysis and enhanced thrombosis risk in cardiovascular disease. In trauma, alcohol has been associated with poor clot formation; however, its effect on Fibrinolysis has not been fully investigated. We assessed the association of blood alcohol levels and Fibrinolysis in trauma activation patients. Methods We queried our prospective registry of trauma activations from 2014 to 2016. Associations between viscoelastic measurements [rapid thrombelastography (rTEG)] and blood alcohol level (BAL) were determined and adjusted for confounders by a multinomial logistic regression. Lysis phenotypes were defined by the % lysis in 30 min (LY30) as follows: hyperFibrinolysis ≥ 3%, physiologic 0.9–2.9%, and Fibrinolysis shutdown  150 mg/dL. BAL had a moderate, but significant inverse correlation with LY30 (Rho = − 0.315, p  

  • human neutrophil elastase mediates Fibrinolysis shutdown through competitive degradation of plasminogen and generation of angiostatin
    Journal of Trauma-injury Infection and Critical Care, 2017
    Co-Authors: Christopher D Barrett, Hunter B. Moore, Anirban Banerjee, Christopher C. Silliman, Ernest E Moore, Michael B Yaffe
    Abstract:

    Background A subset of trauma patients undergo Fibrinolysis shutdown rather than pathologic hyperFibrinolysis, contributing to organ failure. The molecular basis for Fibrinolysis shutdown in trauma is incompletely understood. Elastase released from primed/activated human neutrophils (HNE) has historically been described as fibrin(ogen)olytic. However, HNE can also degrade plasminogen (PLG) to angiostatin (ANG), retaining the kringle domains but not the proteolytic function, and could thereby compete for generation of active plasmin by tissue plasminogen activator (tPA). We hypothesized that HNE can drive Fibrinolysis shutdown rather than Fibrinolysis. Methods Turbidometry was performed using light scatter (λ = 620 nm) in a purified fibrinogen + PLG system and in healthy citrate plasma clotted with Ca/thrombin ± tPA, ±HNE, and ±ANG to evaluate HNE effects on Fibrinolysis, quantified by time to transition midpoint (Tm). ΔTm from control is reported as percent of control ±95% CI. Purified HNE coincubated with PLG or tPA was analyzed by western blot to identify cleavage products. Exogenous HNE was mixed ex vivo with healthy volunteer blood (n = 7) and used in TEG ± tPA to evaluate effects on Fibrinolysis. Results HNE did not cause measurable Fibrinolysis on fibrin clots, clotted plasma, or whole blood as assessed by turbidometry or TEG in the absence of tPA. Upon tPA treatment, all three methods of evaluating Fibrinolysis showed delays and decreases in Fibrinolysis caused by HNE relative to control: fibrin clot turbidometry ΔTm = 110.7% (CI 105.0-116.5%), clotted citrate plasma (n = 6 healthy volunteers) ΔTm = 126.1% (CI 110.4-141.8%), and whole blood native TEG (n = 7 healthy volunteers) with ΔLY30 = 28% (p = 0.043). Western blot analysis of HNE-PLG co-incubation confirmed that HNE generates angiostatin K1-3, and plasma turbidity assays treated with angiostatin K1-3 delayed Fibrinolysis. Conclusion HNE degrades PLG and generates angiostatin K1-3, which predominates over HNE cleavage of fibrin(ogen). These findings suggest that neutrophil release of elastase may underlie trauma-induced fibrinolytic shutdown.

  • rationale for the selective administration of tranexamic acid to inhibit Fibrinolysis in the severely injured patient
    Transfusion, 2016
    Co-Authors: Hunter B. Moore, Anirban Banerjee, Ernest E Moore, Angela Sauaia, Eduardo Gonzalez, Christopher C. Silliman
    Abstract:

    Postinjury Fibrinolysis can manifest as three distinguishable phenotypes: 1) hyperFibrinolysis, 2) physiologic, and 3) hypoFibrinolysis (shutdown). HyperFibrinolysis is associated with uncontrolled bleeding due to clot dissolution; whereas, Fibrinolysis shutdown is associated with organ dysfunction due to microvascular occlusion. The incidence of Fibrinolysis phenotypes at hospital arrival in severely injured patients is: 1) hyperFibrinolysis 18%, physiologic 18%, and shutdown 64%. The mechanisms responsible for dysregulated Fibrinolysis following injury remain uncertain. Animal work suggests hypoperfusion promotes Fibrinolysis, while tissue injury inhibits Fibrinolysis. Clinical experience is consistent with these observations. The predominant mediator of postinjury hyperFibrinolysis appears to be tissue plasminogen activator (tPA) released from ischemic endothelium. The effects of tPA are accentuated by impaired hepatic clearance. Fibrinolysis shutdown, on the other hand, may occur from inhibition of circulating tPA, enhanced clot strength impairing the binding of tPA and plasminogen to fibrin, or the inhibition of plasmin. Plasminogen activator inhibitor -1 (PAI-1) binding of circulating tPA appears to be a major mechanism for postinjury shutdown. The sources of PAI-1 include endothelium, platelets, and organ parenchyma. The laboratory identification of Fibrinolysis phenotype, at this moment, is best determined with viscoelastic hemostatic assays (TEG, ROTEM). While D-dimer and plasmin antiplasmin (PAP) levels corroborate Fibrinolysis, they do not provide real-time assessment of the circulating blood capacity. Our clinical studies indicate that Fibrinolysis is a very dynamic process and our experimental work suggests plasma first resuscitation reverses hyperFibrinolysis. Collectively, we believe recent clinical and experimental work suggest antifibrinolytic therapy should be employed selectively in the acutely injured patient, and optimally guided by TEG or ROTEM.

  • acute Fibrinolysis shutdown after injury occurs frequently and increases mortality a multicenter evaluation of 2 540 severely injured patients
    Journal of The American College of Surgeons, 2016
    Co-Authors: Hunter B. Moore, Ernest E Moore, Angela Sauaia, Eduardo Gonzalez, Ioannis N Liras, John A Harvin, John B Holcomb, Bryan A Cotton
    Abstract:

    Background Fibrinolysis is a physiologic process that maintains microvascular patency by breaking down excessive fibrin clot. HyperFibrinolysis is associated with a doubling of mortality. Fibrinolysis shutdown, an acute impairment of Fibrinolysis, has been recognized as a risk factor for increased mortality. The purpose of this study was to assess the incidence and outcomes of Fibrinolysis phenotypes in 2 urban trauma centers. Study Design Injured patients included in the analysis were admitted between 2010 and 2013, were 18 years of age or older, and had an Injury Severity Score (ISS) > 15. Admission Fibrinolysis phenotypes were determined by the clot lysis at 30 minutes (LY30): shutdown ≤ 0.8%, physiologic 0.9% to 2.9%, and hyperFibrinolysis ≥ 3%. Logistic regression was used to adjust for age, arrival blood pressure, ISS, mechanism, and facility. Results There were 2,540 patients who met inclusion criteria. Median age was 39 years (interquartile range [IQR] 26 to 55 years) and median ISS was 25 (IQR 20 to 33), with a mortality rate of 21%. Fibrinolysis shutdown was the most common phenotype (46%) followed by physiologic (36%) and hyperFibrinolysis (18%). HyperFibrinolysis was associated with the highest death rate (34%), followed by shutdown (22%), and physiologic (14%, p Conclusions Fibrinolysis shutdown is the most common phenotype on admission and is associated with increased mortality. These data provide additional evidence of distinct phenotypes of coagulation impairment and that individualized hemostatic therapy may be required.

  • Hemolysis exacerbates hyperFibrinolysis, whereas platelolysis shuts down Fibrinolysis: evolving concepts of the spectrum of Fibrinolysis in response to severe injury.
    Shock, 2015
    Co-Authors: Hunter B. Moore, Anirban Banerjee, Ernest E Moore, Angela Sauaia, Eduardo Gonzalez, Kirk C. Hansen, Monika Dzieciatkowska, Michael P. Chapman, Bernadette F. West, Christopher C. Silliman
    Abstract:

    ABSTRACTIntroduction: We have recently identified a spectrum of Fibrinolysis in response to injury, in which there is increased mortality in patients who have either excessive Fibrinolysis (hyperFibrinolysis [HF]) or impaired Fibrinolysis (shutdown). The regulation of the fibrinolytic system after t