Discontinuation and management of direct-acting anticoagulants for emergency procedures

AbstractPatients taking direct oral anticoagulants (DOACs) who then need an emergency invasive procedure require specialized management strategies. Appropriate patient evaluation includes assessment of the current anticoagulation state, including timing of the last dose. DOACs require particular coagulation assays to measure anticoagulation levels accurately, although standard coagulation screening tests may provide qualitative guidance. Specialty societies have endorsed general recommendations for patient management to promote hemostasis in anticoagulated patients requiring surgery or other invasive procedures. These include general stopping rules (such as ≥24 hours for low-risk procedures and ≥48 hours for high-risk surgery with normal renal function) for elective procedures. Bridging therapy when oral anticoagulant treatment is interrupted has recently been questioned, depending on the clinical scenario. Novel agents for the reversal of DOAC-induced anticoagulation have recently been developed. Idarucizumab, a humanized monoclonal antibody fragment that selectively binds dabigatran, was recently approved for clinical use in patients with life-threatening or uncontrolled bleeding, and for patients requiring emergency interventions. Idarucizumab can streamline the pre- and periprocedural anticoagulation management of dabigatran-treated patients, as it provides fast, complete, and sustainable reversibility. Andexanet alfa is an inactive, decoy factor Xa (FXa) molecule that binds FXa inhibitors, and ciraparantag is a synthetic molecule designed to bind fractionated and unfractionated heparins, and each of the currently approved DOACs. As clinical development of the additional anti-FXa-specific anticoagulant reversal agents proceeds, the respective role of each in the management of emergency bleeding events and invasive procedures will be better defined, and it is hoped they will make important contributions to patient care

Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants.

Perioperative management of patients treated with the non-vitamin K antagonist oral anticoagulants is an ongoing challenge. Due to the lack of good clinical studies involving adequate monitoring and reversal therapies, management requires knowledge and understanding of pharmacokinetics, renal function, drug interactions, and evaluation of the surgical bleeding risk. Consideration of the benefit of reversal of anticoagulation is important and, for some low risk bleeding procedures, it may be in the patient's interest to continue anticoagulation. In case of major intra-operative bleeding in patients likely to have therapeutic or supra-therapeutic levels of anticoagulation, specific reversal agents/antidotes would be of value but are currently lacking. As a consequence, a multimodal approach should be taken which includes the administration of 25 to 50 U/kg 4-factor prothrombin complex concentrates or 30 to 50 U/kg activated prothrombin complex concentrate (FEIBA®) in some life-threatening situations. Finally, further studies are needed to clarify the ideal therapeutic intervention

Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO

During extracorporeal membrane oxygenation (ECMO), a delicate balance is required to titrate systemic anticoagulation to prevent thrombotic complications within the circuit and prevent bleeding in the patient. Despite focused efforts to achieve this balance, the frequency of both thrombotic and bleeding events remains high. Anticoagulation is complicated to manage in this population due to the complexities of the hemostatic system that are compounded by age-related developmental hemostatic changes, variable effects of the etiology of critical illness on hemostasis, and blood-circuit interaction. Lack of high-quality data to guide anticoagulation management in ECMO patients results in marked practice variability among centers. One aspect of anticoagulation therapy that is particularly challenging is the use of antithrombin (AT) supplementation for heparin resistance. This is especially controversial in the neonatal and pediatric population due to the baseline higher risk of bleeding in this cohort. The indication for AT supplementation is further compounded by the potential inaccuracy of the diagnosis of heparin resistance based on the standard laboratory parameters used to assess heparin effect. With concerns regarding the adverse impact of bleeding and thrombosis, clinicians and institutions are faced with making difficult, real-time decisions aimed at optimizing anticoagulation in this setting. In this clinically focused review, the authors discuss the complexities of anticoagulation monitoring and therapeutic intervention for patients on ECMO and examine the challenges surrounding AT supplementation given both the historical and current perspectives summarized in the literature on these topics

Pharmacological Comparison of Human Internal Mammary Artery and Radial Artery in Terms of Conduits for Revascularization

Internal mammary arteries (IMA) are routinely used for coronary artery bypass grafting (CABG), but can exhibit impairment of endothelium-dependent vascular relaxation. The use of radial artery (RA) grafts for CABG has been recently reintroduced. The long-term patency of these grafts may depend on the ability of these vessels to produce endotheliumderived nitric oxide (NO). We therefore sought to determine if the RA exhibits better endothelial function compared with IMA harvested from the same patient. Using the organ bath technique, vessels were preconstricted with the thromboxane A2 analogue (U46619) and exposed to increasing concentrations of either acetylcholine (ACh ), calcium ionophore A23187 (A23187), or nitroglycerin (NTG). We prepared the rubbed RA for comparison of between RA with and without endothelium on response to ACh relaxation. KCI and U46619 constricted RA (11.3ﾂｱ4.9g and 16.0ﾂｱ4.3g respectively) more than IMA(2.4ﾂｱ1.4g and 4.5ﾂｱ1.7 respectively). Both RA and IMA relaxed 100% of the preconstricted tension to NTG. ACh induced less relaxation in the IMA(28ﾂｱ24%) when compared with the RA(49ﾂｱ16%)(p<0.05). A23187 demonstrated relaxation in both the RA(86ﾂｱ14%)and IMA(76ﾂｱ18%), but there was no statistical difference. RA without endothelium showed same response to ACh as IMAs. Compared with the IMA, the RA has better ACh induced endothelium-dependent relaxation. This pathway mainly involves NO production which also inhibits the atherosclerotic process. Therefore, the RA may provide longer term graft patency than IMA

Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .)

Race-Related disparities in COVID-19 thrombotic outcomes: Beyond social and economic explanations

African Americans (AAs) have worse COVID-19-related outcomes than Caucasians and Asians, a disparity currently attributed to potential social and economic factors. In this commentary, we endeavor to examine important race-related differences in intrinsic thrombogenicity as another significant contributing factor and propose objective hemostasis assessments to address racial disparities in COVID-19 outcomes.Funding: Platelet and Thrombosis Research, LLC. Competing Interest: Dr. Kreutz has received consulting fees from Haemonetics. Dr. Jeong has received honoraria for lectures from AstraZeneca, Sanofi-Aventis, Daiichi Sankyo/Lilly, Haemonetics, Otsuka, Han-mi Pharmaceuticals and Yuhan Pharmaceuticals; and research grants or support from AstraZeneca, Korean Society of Interventional Cardiology, Han-mi Pharmaceuticals, Yuhan Pharmaceuticals, Otsuka and Haemonetics. Dr. Levy reports honoraria for advisory boards from Instrumentation Labs, Merck, Octapharma, and Janssen. Dr. Gurbel reports grants and personal fees from Bayer HealthCare LLC, Otitopic Inc, Amgen, Janssen, and US WorldMeds LLC; grants from Instrumentation Laboratory, Haemonetics, Medicure Inc, Idorsia Pharmaceuticals, and Hikari Dx; personal fees from UpToDate; Dr Gurbel is a relator and expert witness in litigation involving clopidogrel; in addition, Dr. Gurbel has two patents, Detection of restenosis risk in patients and Assessment of cardiac health and thrombotic risk in a patient. Other authors report no disclosure

Polymerized bovine hemoglobin solution as a replacement for allogeneic red blood cell transfusion after cardiac surgery: Results of a randomized, double-blind trial

AbstractBackground: Blood loss leading to reduced oxygen-carrying capacity is usually treated with red blood cell transfusions. This study examined the hypothesis that a hemoglobin-based oxygen-carrying solution can serve as an initial alternative to red blood cell transfusion. Methods: In a randomized, double-blind efficacy trial of HBOC-201, a total of 98 patients undergoing cardiac surgery and requiring transfusion were randomly assigned to receive either red blood cell units or HBOC-201 (Hemopure; Biopure Corporation, Cambridge, Mass) for the first three postoperative transfusions. Patients were monitored before and after transfusion, at discharge, and at 3 to 4 weeks after the operation for subsequent red blood cell use, hemodynamics, and clinical laboratory parameters. Results: The use of HBOC-201 eliminated the need for red blood cell transfusions in 34% of cases (95% confidence interval 21%-49%). Patients in the HBOC group received a mean of 1.72 subsequent units of red blood cells; those who received red blood cells only received a mean of 2.19 subsequent units (P =.05). Hematocrit values were transiently lower in the HBOC group but were similar in the two groups at discharge and follow-up. Oxygen extraction was greater in the HBOC group (P =.05). Mean increases in blood pressure were greater in the HBOC group, but not significantly so. Conclusion: HBOC-201 may be an initial alternative to red blood cell transfusions for patients with moderate anemia after cardiac surgery. In a third of cases, HBOC-201 eliminated the need for red blood cell transfusion, although substantial doses were needed to produce this modest degree of blood conservation.J Thorac Cardiovasc Surg 2002;124:35-4

Viscoelastometric Testing to Assess Hemostasis of COVID-19: A Systematic Review

Infection by SARS-CoV-2 is associated with a high risk of thrombosis. The laboratory documentation of hypercoagulability and impaired fibrinolysis remains a challenge. Our aim was to assess the potential usefulness of viscoelastometric testing (VET) to predict thrombotic events in COVID-19 patients according to the literature. We also (i) analyzed the impact of anticoagulation and the methods used to neutralize heparin, (ii) analyzed whether maximal clot mechanical strength brings more information than Clauss fibrinogen, and (iii) critically scrutinized the diagnosis of hypofibrinolysis. We performed a systematic search in PubMed and Scopus databases until 31st December 2020. VET methods and parameters, and patients' features and outcomes were extracted. VET was performed for 1063 patients (893 intensive care unit (ICU) and 170 non-ICU, 44 studies). There was extensive heterogeneity concerning study design, VET device used (ROTEM, TEG, Quantra and ClotPro) and reagents (with non-systematic use of heparin neutralization), timing of assay, and definition of hypercoagulable state. Notably, only 4 out of 25 studies using ROTEM reported data with heparinase (HEPTEM). The common findings were increased clot mechanical strength mainly due to excessive fibrinogen component and impaired to absent fibrinolysis, more conspicuous in the presence of an added plasminogen activator. Only 4 studies out of the 16 that addressed the point found an association of VETs with thrombotic events. So-called functional fibrinogen assessed by VETs showed a variable correlation with Clauss fibrinogen. Abnormal VET pattern, often evidenced despite standard prophylactic anticoagulation, tended to normalize after increased dosing. VET studies reported heterogeneity, and small sample sizes do not support an association between the poorly defined prothrombotic phenotype of COVID-19 and thrombotic events