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Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

ABSTRACT: Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, we solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecule FXa inhibitors. We demonstrate that combinations of 11F7t and catalytic-site FXa inhibitors enhance anticoagulation in purified reaction mixtures and plasma. Aptamer-drug combinations prevented clot formation as effectively as UFH in human blood circulated in an extracorporeal oxygenator circuit that mimicked CPB, while avoiding side effects of UFH. An antidote could promptly neutralize the anticoagulant effects of both FXa inhibitors. Our results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone.

SUBMITTER: Gunaratne R

PROVIDER: S-EPMC6349032 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

Gunaratne Ruwan R Kumar Shekhar S Frederiksen James W JW Stayrook Steven S Lohrmann Jens L JL Perry Kay K Bompiani Kristin M KM Chabata Charlene V CV Thalji Nabil K NK Ho Michelle D MD Arepally Gowthami G Camire Rodney M RM Krishnaswamy Sriram S Sullenger Bruce A BA

Nature biotechnology 20180604 7

Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, we solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecul ...[more]

PMID: 29863725

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Project description:Despite more than a half century of "safe" cardiopulmonary bypass (CPB), the evidence base surrounding the conduct of anticoagulation for CPB has not been organized into a succinct guideline. For this and other reasons, there is enormous practice variability relating to the use and dosing of heparin, monitoring heparin anticoagulation, reversal of anticoagulation, and the use of alternative anticoagulants. To address this and other gaps, the Society of Thoracic Surgeons (STS), the Society of Cardiovascular Anesthesiologists (SCA), and the American Society of Extracorporeal Technology (AmSECT) developed an Evidence Based Workgroup. This was a group of interdisciplinary professionals gathered together to summarize the evidence and create practice recommendations for various aspects of CPB. To date, anticoagulation practices in CPB have not been standardized in accordance with the evidence base. This clinical practice guideline was written with the intent to fill the evidence gap and to establish best practices in anticoagulation for CPB using the available evidence. To identify relevant evidence a systematic review was outlined and literature searches were conducted in PubMed® using standardized MeSH terms from the National Library of Medicine list of search terms. Search dates were inclusive of January 2000 to December 2015. The search yielded 833 abstracts which were reviewed by two independent reviewers. Once accepted into the full manuscript review stage, two members of the writing group evaluated each of 286 full papers for inclusion eligibility into the guideline document. Ninety-six manuscripts were included in the final review. In addition, 17 manuscripts published prior to 2000 were included to provide method, context, or additional supporting evidence for the recommendations as these papers were considered sentinel publications. Members of the writing group wrote and developed recommendations based on review of the articles obtained and achieved more than two thirds agreement on each recommendation. The quality of information for a given recommendation allowed assessment of the level of evidence as recommended by the AHA/ACCF Task Force on Practice Guidelines. Recommendations were written in the three following areas 1) Heparin dosing and monitoring for initiation and maintenance of CPB, 2) Heparin contraindications and heparin alternatives, 3) Reversal of anticoagulation during cardiac operations. It is hoped that this guideline will serve as a resource and will stimulate investigators to conduct more research and expand upon the evidence base on the topic of anticoagulation for CPB.

Project description:Essentials Heparin-protamine balance (HPB) modulates bleeding after neonatal cardiopulmonary bypass (CPB). HPB was examined in 44 neonates undergoing CPB. Post-operative bleeding occurred in 36% and heparin rebound in 73%. Thrombin-initiated fibrin clot kinetic assay and partial thromboplastin time best assessed HPB.SummaryBackground Neonates undergoing cardiopulmonary bypass (CPB) are at risk of excessive bleeding. Blood is anticoagulated with heparin during CPB. Heparin activity is reversed with protamine at the end of CPB. Paradoxically, protamine also inhibits blood coagulation when it is dosed in excess of heparin. Objectives To evaluate heparin-protamine balance in neonates undergoing CPB by using research and clinical assays, and to determine its association with postoperative bleeding. Patients/Methods Neonates undergoing CPB in the first 30 days of life were studied. Blood samples were obtained during and after surgery. Heparin-protamine balance was assessed with calibrated automated thrombography, thrombin-initiated fibrin clot kinetic assay (TFCK), activated partial thromboplastin time (APTT), anti-FXa activity, and thromboelastometry. Excessive postoperative bleeding was determined by measurement of chest tube output or the development of cardiac tamponade. Results and Conclusions Of 44 neonates enrolled, 16 (36%) had excessive postoperative bleeding. The TFCK value was increased. By heparin in neonatal blood samples, but was only minimally altered by excess protamine. Therefore, it reliably measured heparin in samples containing a wide range of heparin and protamine concentrations. The APTT most closely correlated with TFCK results, whereas anti-FXa and thromboelastometry assays were less correlative. The TFCK and APTT assay also consistently detected postoperative heparin rebound, providing an important continued role for these long-established coagulation tests in the management of postoperative bleeding in neonates requiring cardiac surgical repair. None of the coagulation tests predicted the neonates who experienced postoperative bleeding, reflecting the multifactorial causes of bleeding in this population.

Project description:ObjectivesThe study objectives were to describe the incidence, risk factors, and outcomes of acute kidney injury after cardiopulmonary bypass in Jamaica.MethodWe performed a review of the medical records of adult patients (aged ≥ 18 years) with no prior dialysis requirement undergoing cardiopulmonary bypass at the University Hospital of the West Indies, Mona, between January 1, 2016, and June 30, 2019. Demographic, preoperative, intraoperative, and postoperative data were abstracted. Acute kidney injury was defined using Kidney Disease Improving Global Outcomes criteria. The primary outcomes were acute kidney injury incidence and all-cause 30-day mortality. Multivariable logistic regression and Cox proportional analyses were used to examine the association between the acute kidney injury risk factors and the primary outcome.ResultsData for 210 patients (58% men, mean age 58.1 ± 12.9 years) were analyzed. Acute kidney injury occurred in 80 patients (38.1%), 44% with Kidney Disease Improving Global Outcomes I, 33% with Kidney Disease Improving Global Outcomes II, and 24% with Kidney Disease Improving Global Outcomes III. From multivariable logistic regression models, European System for Cardiac Operative Risk Evaluation II (odds ratio, 1.19; 95% confidence interval, 1.01-1.39 per unit), bypass time (odds ratio, 1.94; 95% confidence interval, 1.40-2.67 per hour), perioperative red cell transfusion (odds ratio, 3.03; 95% confidence interval, 1.36-6.76), and postoperative neutrophil lymphocyte ratio (odds ratio, 1.65; 95% confidence interval, 1.01-2.68 per 10-unit difference) were positively associated with acute kidney injury. Acute kidney injury resulted in greater median hospital stay (18 vs 11 days, P < .001) and intensive care unit stay (5 vs 3 days, P < .001), and an 8-fold increase in 30-day mortality (hazard ratio, 8.15; 95% confidence interval, 2.76-24.06, P < .001).ConclusionsAcute kidney injury after cardiopulmonary bypass surgery occurs frequently in Jamaica and results in poor short-term outcomes. Further studies coupled with quality interventions to reduce the mortality of those with acute kidney injury are needed in the Caribbean.

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Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

Publications

Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

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