Reversal of Anticoagulation

Patients treated with warfarin for therapeutic anticoagulation present a challenge for the perioperative management of urgent and emergent surgery. Anticoagulation must be reversed prior to most surgical procedures to prevent intraoperative bleeding. The purpose of this module is to review the options for urgent reversal of warfarin anticoagulation and the indications for each reversal agent. Selection of the appropriate agent is important to reduce unnecessary complications of treatment and to achieve optimal reversal of anticoagulation. When urgent surgery is required for patients taking warfarin, intravenous vitamin K1 should be used for procedures that can be delayed for six to 12hr. Vitamin K1 results in the activation of existing clotting factors rather than requiring the synthesis of new proteins, which allows for its relatively rapid onset of action. Intravenous vitamin K1 acts more quickly than oral administration, with reversal of anticoagulation occurring within six to 12hr vs 18-24hr, respectively. If surgery cannot be delayed, prothrombin complex concentrates (PCCs) should be given, and intravenous vitamin K1 should be infused concurrently to ensure sustained reversal of anticoagulation. The duration of action of both PCCs and plasma is six hours due to the short half-life of factor VII. Prothrombin complex concentrates contain small amounts of heparin and are contraindicated in patients with heparin-induced thrombocytopenia. Plasma should be used only if PCCs are unavailable or are contraindicated. Reversal of warfarin anticoagulation can be achieved in a safe and timely manner when the appropriate agent is selected and administered correctly.

Reversal of Anticoagulation By Ciraparantag: Time to Onset and Duration of Effect

Reversal of Trauma-Induced Bleeding and Anticoagulation with a Dabigatran-Specific Antidote (idarucizumab) As Assessed By Shed and Washed Blood Tests in a Pig Model of Supratherapeutic Anticoagulation and Trauma

Specific mass spectrometry and direct activated factor X (Xa)- and thrombin inhibition assays do not allow determination of the reversal of anticoagulant effects of non-vitamin K direct oral anticoagulants (NOACs) by prothrombin complex concentrate (PCC). The objective of this study was the evaluation of the applicability of a variety of commercially available global coagulation assays in analyzing the reversal of NOAC anticoagulation by PCC. Plasma and whole blood were spiked with apixaban or dabigatran and PCC was added to these samples. Prothrombin time (PT), modified PT (mPT), activated partial prothrombin time (APTT), thrombography (CAT method) and thromboelastography (ROTEM, TEG) were performed. Assays triggered by contact activation (APTT, INTEM) did not show inhibitor reversal by PCC. Assays triggered by tissue factor (TF) showed NOAC type and NOAC concentration dependent anticoagulation reversal effects of PCC ranging from partial normalization to overcorrection of the following parameters: clotting or reaction time (PT, mPT TEG-TF, EXTEM, FIBTEM); angle in thromboelastography (TEG-TF); thrombin generation (CAT) lag time, endogenous thrombin potential (ETP) and peak thrombin. Extent of reversal was assay reagent dependent. ETP (5 pM TF) was the only parameter showing complete reversal of anticoagulation by PCC for all NOACs ranging from 200 to 800 μg/L. ETP fits with the concept that reversal assessment of NOAC anticoagulation by PCC should be based on measurements on the clotting potential or thrombin generating potential of the plasma or whole blood patient sample. Low sensitivity of ETP for NOACs and its correlation with bleeding are issues that remain to be resolved.

Efficacy and safety of Prothrombin Complex Concentrates Weight-Based Dosing for Reversal of Warfarin Anticoagulation

Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation

Protamine reversal of anticoagulation achieved with a low molecular weight heparin. The effects on eicosanoids, clotting and complement factors

Prothrombin Complex Concentrates (PCCs) Have Limited Effect on TF-Initiated Thrombin Generation in FXa Inhibitor-Anticoagulated Plasma: In Vitro Comparison between Direct Reversal By Andexanet Alfa and “Work Around” By PCCs

Emergent anticoagulation reversal and BP control are key for ICH

Direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited. To evaluate the safety and outcomes of DOAC reversal agents among patients with ICH. PubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022. The eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model. The primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent. A total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events. In the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.

The management of coumarin-induced over-anticoagulation Annotation.

Department of Anesthesia, Harvard Medical School at Beth Israel Hospital, and the Departments of Anesthesia and Medicine, Harvard Medical School at the Massachusetts General Hospital, Boston, Massachusetts

Warfarin-reversal: results of a phase III study with pasteurised, nanofiltrated prothrombin complex concentrate

Intracerebral haemorrhage (ICH) secondary to use of anti-coagulants is one of the fearsome complications. Haemorrhage within the intracranial space due to such anti-coagulants results in expansion of the intracranial bleeding despite the reversal of anti-coagulants. Hence, timely surgical intervention can be lifesaving. An elderly female who was undergoing management for her deranged coagulation parameters was found to be in a state of features suggestive of stroke. The patient was on regular anti-coagulants medication for her cardiology issues. Computed tomography (CT) scan showed intracranial haemorrhage, which underwent expansion on same day; hence decompressive craniectomy was done. During further stay in the ICU patient's Glasgow coma scale fluctuated but symptomatic improvement was noted. Anti-coagulants adjustment was made by a cardiologist and further, there was no expansion of intracranial bleeding within normal coagulation parameters. Anti-coagulants are rampantly used in several cases. Despite the several complications, there is a desperate need for such medications for the betterment of the patient's condition. Pharmacological management is a major modality in the reversal of oral anti-coagulants (OAC)-induced ICH, but in rare cases in the background of OACs-induced ICH, there occurs expansion of haemorrhage. Hence there is a need for neurosurgical intervention, whether it be minimally invasive surgery or decompressive craniectomy. In the background of the low prevalence of OACs-induced ICH, there is an absence of a robust guiding treatment protocol. Furthermore, there exist minimal reported cases which underwent surgical intervention and resulted in a good prognosis.

Efficacy and safety of a prothrombin complex concentrate (Octaplex®) for rapid reversal of oral anticoagulation