Emergency Reversal Of Anticoagulation Research Articles

Code ICH: A Call to Action.

Intracerebral hemorrhage is the most serious type of stroke, leading to high rates of severe disability and mortality. Hematoma expansion is an independent predictor of poor functional outcome and is a compelling target for intervention. For decades, randomized trials aimed at decreasing hematoma expansion through single interventions have failed to meet their primary outcomes of statistically significant improvement in neurological outcomes. A wide range of evidence suggests that ultra-early bundled care, with multiple simultaneous interventions in the acute phase, offers the best hope of limiting hematoma expansion and improving functional recovery. Patients with intracerebral hemorrhage who fail to receive early aggressive care have worse outcomes, suggesting that an important treatment opportunity exists. This consensus statement puts forth a call to action to establish a protocol for Code ICH, similar to current strategies used for the management of acute ischemic stroke, through which early intervention, bundled care, and time-based metrics have substantially improved neurological outcomes. Based on current evidence, we advocate for the widespread adoption of an early bundle of care for patients with intracerebral hemorrhage focused on time-based metrics for blood pressure control and emergency reversal of anticoagulation, with the goal of optimizing the benefit of these already widely used interventions. We hope Code ICH will endure as a structural platform for continued innovation, standardization of best practices, and ongoing quality improvement for years to come.

Coagulopathy and Emergent Reversal of Anticoagulation.

More patients than ever are presenting for urgent or emergent procedures while therapeutically anticoagulated for various medical indications. Medications including warfarin, antiplatelet agents such as clopidogrel, direct oral anticoagulants such as apixaban, and even heparin or heparinoids may be present. Each of these medication classes presents its own challenges when coagulopathy needs to be quickly corrected. This review article presents evidence-based discussions of monitoring and reversal of these medication-induced coagulopathies. In addition, there will be a brief discussion of other potential coagulopathies that may be encountered in providing acute care anesthesia.

Emergency Reversal of Anticoagulation.

Owing to the propensity of anticoagulated patients to bleed, a strategy for reversal of anticoagulation induced by any of the common agents is essential. Many patients are anticoagulated with a variety of agents, including warfarin, low molecular weight heparin, and the direct oral anticoagulants such as factor Xa and factor IIa inhibitors. Patients may also be using antiplatelet agents. Recommendations to reverse bleeding in these patients are constantly evolving with the recent development of specific reversal agents. A working knowledge of hemostasis and the reversal of anticoagulation and antiplatelet drugs is required for every emergency department provider. This article reviews these topics and presents the currently recommended strategies for dealing with bleeding in the anticoagulated patient.

Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study.

Oral factor Xa (fXa) inhibitor-related bleeding is a concerning drug safety problem. There is considerable controversy surrounding available reversal strategies. The recently approved reversal agent andexanet alfa has limited data, an unclear safety profile, and imparts a substantial financial burden. This has led to the off-label use of four-factor prothrombin complex concentrates (4F-PCC) for this indication. This study aimed to assess the safety and efficacy of 4F-PCC for the management of major bleeding related to oral fXa inhibitors. This observational, retrospective study included adult patients admitted from 2014 to 2018 who received 4F-PCC (Kcentra®) for fXa inhibitor-related major bleeding. Efficacy was assessed using criteria described by Sarode et al. Secondary outcomes included the incidence of thromboembolism, mortality, and a cost analysis comparing 4F-PCC to andexanet alfa for reversal of oral fXa inhibitors. Thirty-one patients received 4F-PCC for major bleeding associated with apixaban (55%) or rivaroxaban (45%). Intracranial hemorrhage (58%) and pericardial effusion (16%) accounted for the majority of bleeding events. Most patients received a single weight-based 4F-PCC dose of 25 units/kg (38.7%) or 50 units/kg (51.6%). Effective hemostasis was achieved in 80.6% of patients. Five patients (16%) died due to acute bleeding and no thromboembolic events were observed. Administration of 4F-PCC was effective for most patients requiring emergent reversal of anticoagulation with apixaban or rivaroxaban and was associated with a low risk of thromboembolic events. Considerable cost differences limit the use of andexanet alfa and may warrant further study of 4F-PCC for fXa inhibitor reversal.

Four-Factor Prothrombin Complex Concentrate (4F-PCC) Is Superior to Three-Factor Prothombin Comlex Concentrates (3F-PCC) for Reversal of Coumarin Anticoagulation

Due to its wide range of therapeutic indications approximately 2.5 million adults and children are currently receiving vitamin K antagonist (VKA) therapy in the US (Pengo et al., 2006). Bleeding is the major risk of anticoagulation, with an incidence of major hemorrhage in VKA-treated patients of 1.7-3.4% per year (Schulman et al., 2008). The 4-factor prothrombin complex concentrate (4F-PCC), which contains the human coagulation factors II, VII, IX and X together with the endogenous inhibitor proteins S and C, is indicated for the urgent reversal of acquired coagulation factor deficiency induced by VKA (e.g. warfarin or coumarin) therapy in adult patients with acute major bleeding. In contrast, the 3-factor prothrombin complex concentrates (3F-PCC), which contain factors II, IX, X and only minimal amounts of factor VII, are only indicated for the prevention and control of hemorrhagic episodes in hemophilia B patients. Nevertheless, the use of 3F-PCC for correcting hemostasis following warfarin overdose has been discussed (Imberti et al. 2011, Holland et al. 2009). However, the lack of factor VII in these 3F-PCC products has raised questions about efficacy in comparison to 4F-PCC (Sarode et al. 2012). To date, no studies have directly compared 3F-PCC vs. 4F-PCC regarding their efficacy for reversal of VKA anticoagulation.Therefore, this study was conducted as a head-to-head comparison of 4F-PCC and 3F-PCC for effective reversal of VKA (coumarin) induced anticoagulation using an established rat model of acute bleeding (Dickneite et al. 2007).Rats received an oral dose of 2.5 mg/kg phenprocoumon. At 15.75 hours post dosing, animals were treated with a single intravenous dose of saline, 4F-PCC (Beriplex® P/N, Kcentra®, CSL Behring) or 3F-PCC (Bebulin® VH and Profilnine® SD). Study endpoints included bleeding following tail clip, activated partial thromboplastin time (aPTT), and prothrombin time (PT). In addition, the plasma levels of vitamin K dependent coagulation factors were determined.Acute coumarin anticoagulation of rats induced a rise in median bleeding time by ≥2 fold from an average of 823 to 1800 seconds (max. observation period) compared to untreated animals. In parallel, PT and aPTT were prolonged from 8.9 to 29.9 seconds and 14.5 to 25.5 seconds, respectively. Treatment with 4F-PCC was able to fully and statistically significantly reverse bleeding, achieving average bleeding times of 676 seconds. In parallel, the elevation in PT was reversed to 15.1 seconds. In contrast, the 3F-PCCs were not or only partially able to reduce coumarin induced bleeding with average bleeding times of 1398 and 1708 seconds post treatment. This also correlated with inferior reductions in PT which achieved minimum levels of 23.8 and 29.5 seconds. There was no reduction in aPTT seen for any treatment option.In conclusion, this first direct comparison of 4F-PCC and 3F-PCCs for the reversal of VKA anticoagulation in a rat model of acute bleeding suggests that replenishment of all vitamin K-dependent coagulation factors including factor VII as achieved using a 4F-PCC may result in superior efficacy compared to the use of 3F-PCCs.ReferencesDickneite G: Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation.Thromb Res 119:643–651, 2007Holland L, Warkentin TE, Refaai M, et al. Suboptimal effect of three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic INR due to warfarin overdose. Transfusion 2009;49:1171–7.Imberti D, Barillari G, Biasioli C, et al. Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus 2011;9:148–55.Pengo V, Pegoraro C, Cucchini U, IIiceto S. The management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis 2006;21:73-7Sarode R, Matevosyan K, Bhagat R, Rutherford C, Madden C, Beshay JE. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage.J Neurosurg 116:491–497, 2012Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: american college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;13:257S-98S DisclosuresHerzog:CSL Behring GmbH: Employment. Off Label Use: Non-clinical data on the use of 3F-PCC for reversal of VKA . Kaspereit:CSL Behring GmbH: Employment. Krege:CSL Behring GmbH: Employment. Niebl:CSL Behring GmbH: Employment. Schulte:CSL Behring GmbH: Employment. Dickneite:CSL Behring GmbH: Employment.

Emergency reversal of anticoagulation: novel agents.

Historically, oral anticoagulation involved the administration of vitamin K antagonists, such as warfarin. However, because of the need for frequent monitoring and the desire for safer anticoagulants, several novel oral anticoagulants have been developed. These newer agents include the factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban), along with the direct thrombin inhibitors (eg, dabigatran). This manuscript provides a brief overview of their uses and mechanisms of action, along with a review of currently available evidence for reversal strategies when life-threatening bleeding occurs.

New oral anticoagulant drugs: real-world data.

Oral anticoagulants or ‘blood thinners’ were proposed in 400 BC during the time of Hippocrates [1]. The first paper entitled ‘Coumadin (warfarin) sodium – a new anticoagulant’ was published in 1956 [2]. Despite its limitations, coumadin stood the test of time. Ximelagatran, a very potent oral thrombin inhibitor, licensed in Europe for a short time, was later withdrawn in 2006 for concerns of causing hepatotoxicity [3].

Reversing Dabigatran in Life-Threatening Bleeding Occurring During Cardiac Ablation With Factor Eight Inhibitor Bypassing Activity

We report a case of a patient receiving dabigatran who developed a life-threatening bleeding complication during cardiac ablation that rapidly resolved after administration of Factor Eight Inhibitor Bypassing Activity (FEIBA). Therapeutic anticoagulation with warfarin during cardiac ablation has been shown to reduce the risk of stroke and systemic embolism. Cardiac tamponade is a potentially life-threatening procedural complication requiring emergent reversal of anticoagulation and pericardiocentesis. Dabigatran is superior to warfarin in preventing stroke and systemic embolism in nonvalvular atrial fibrillation, but has not been evaluated for use during cardiac ablation. Dabigatran is without a known reversal agent and, should tamponade occur during ablation, it is unclear what reversal strategy could be used to establish hemostasis. A 67-year-old man with history of atrial fibrillation with rapid ventricular rate, two previous atrial fibrillation ablations, and prescribed dabigatran 150 mg bid was admitted for an atrial fibrillation ablation procedure. The last dabigatran dose was 7 hours prior to procedure. During the procedure, a transseptal perforation occurred, requiring an emergent pericardiocentesis. Within 60 minutes, approximately 4.5 L of blood was removed via the pericardiocentesis. Low-dose FEIBA (3159 units, 26 U/kg actual body weight) over 15 minutes was administered. Hemostasis was noted within minutes of initiating the infusion with cessation of bleeding after administration was complete. This case report describes the potential ability of a low dose of the activated prothrombin complex concentrate, FEIBA, to reestablish hemostasis independent of the pharmacologic effects of dabigatran. Additional studies are warranted to confirm the findings of our observation.

Emergency reversal of anticoagulation with vitamin K antagonists with 3-factor prothrombin complex concentrates in patients with major bleeding

Major bleeding is a serious and potentially fatal complication of treatment with vitamin K antagonists (VKAs). Prothrombin complex concentrates (PCCs) can substantially shorten the time needed to reverse VKA effects. To determine the efficacy and safety of 3-factor PCCs for the rapid reversal of VKAs in patients with major bleeding. Patients receiving VKAs and suffering from acute major bleeding were eligible for this prospective cohort study if their international normalized ratio (INR) was higher than or equal to 2.0. Stratified 35-50IUkg(-1) PCC doses were infused based on initial INR. A total of 126 patients (62 males; mean age: 74years, range 37-96years) were enrolled. The mean INR at presentation was 3.3 (range 2-11). At 30min after PCC administration the mean INR was 1.4 (range: 0.9-3.1), declining to less than or equal to 1.5 in 75% of patients. The benefit of PCC was maintained for a long time, since in 97% of all post-infusion time points through 96h the mean INR remained lower than or equal to 1.5 (mean: 1.19; range: 0.9-2.3). During hospitalization neither thrombotic complications nor significant adverse events were observed and 12 patients died (10%); none of the deaths was judged to be related to PCC administration. 3-factor PCC administration is an effective, rapid ad safe treatment for the urgent reversal of VKAs in patients with acute major bleeding. Broader use of PCC in this clinical setting appears to be appropriate.

Experience with prothrombin complex for the emergent reversal of anticoagulation in rural geriatric trauma patients

Therapeutic anticoagulation in the geriatric trauma population is increasingly common. Fresh frozen plasma, while the criterion standard for correction, has limited availability and associated transfusion risks. We examined our use of prothrombin complex concentrate for immediate reversal of therapeutically anticoagulated geriatric trauma patients. This was a 1-year, retrospective review of 25 geriatric trauma patients who received either fresh frozen plasma alone or prothrombin complex concentrate and met the inclusion criteria of age >55 years, current warfarin use, and an admission international normalized ratio of >1.5. Fifteen patients received prothrombin complex concentrate and 10 patients received fresh frozen plasma alone. We examined demographics, laboratory values, and blood product use. The mean ages were similar (77 vs 80 years). Patients had similar mean Injury Severity Score (19.1 vs 19.2). Survivor duration of hospital stay (7.7 vs 9.5; P = .37) and duration of stay in the intensive care unit (4.4 vs 7.1; P = .25) trended positively in the prothrombin complex concentrate group. The prothrombin complex concentrate group received fewer units of fresh frozen plasma (1.6 [range, 0-6] vs 2.7 [range, 2-4]; P = .05), with a greater decrease in international normalized ratio (51% vs 43%; P = .05). Six patients (40%) in the prothrombin complex concentrate group avoided fresh frozen plasma transfusion altogether. Prothrombin complex may be used safely and effectively to reverse emergently anticoagulation in geriatric trauma patients.

Emergency reversal of anticoagulation: The real use of prothrombin complex concentrates: A prospective multicenter two year French study from 2006 to 2008

IntroductionProthrombin complex concentrate (PCC) for reversal of vitamin K antagonist (VKA) is the main therapeutic option in cases of life-threatening bleeding. Clinical use of PCC is poorly documented. MethodsWe prospectively assessed PCC use in four French emergency departments during a two year period 2006-2008 before publication of French Guidelines. An appropriate treatment was defined when PCC was recommended, with a dose of PCC above or equal to 20UI/kg, with vitamin K and with an assessment of international normalized ratio (INR) after PCC. Time of diagnosis and PCC administration were collected, as INR values, thromboembolic events within seven days, hospital mortality. Results256 patients received PCC for reversal of OAT. PCC was mainly prescribed for major intracerebral (ICH) or gastrointestinal hemorrhage. An appropriate treatment was observed in 26% of patients. Intra-hospital mortality for major bleeding was 33% for ICH and 26% for non-ICH major bleeding. A PCC dose>20UI/kg was able to reach an INR<1.5 in 65% of patients. For major hemorrhages (70%), time between patient arrival and treatment delivery exceeded three hours in half of cases. Control of INR was omitted in 20% of patients. No patients presented a thromboembolic event. ConclusionA suitable treatment was administered in 26% of patients. A PCC dose of 20-30IU/kg seems adequate in most cases to reverse VKA activity, but both higher and lower doses achieve similar effects. Considerable progress is required to improve PCC administration and control of treatment efficacy, and to shorten time to diagnosis.

Emergency reversal of anticoagulation: from theory to real use of prothrombin complex concentrates. A retrospective Italian experience.

Prothrombin Complex Concentrates (PCC) are administered to normalise blood coagulation in patients receiving oral anticoagulant therapy (OAT). Rapid reversal of OAT is essential in case of major bleeding, internal haemorrhage or surgery.The primary end-point was to evaluate whether PCC in our hospital were being used in compliance with international and national guidelines for the reversal of OAT on an emergency basis. The secondary end-point was to evaluate the efficacy and safety of PCC. All patients receiving OAT who required rapid reversal anticoagulation because they had to undergo emergency surgery or urgent invasive techniques following an overdose of oral anticoagulants were eligible for this retrospective observational study. Forty-seven patients receiving OAT who needed rapid reverse of anticoagulation were enrolled in our study. The patients were divided in two groups: (i) group A (n=23), patients needed haemostatic treatment before neurosurgery after a head injury and (ii) group B (n=24), patients with critical haemorrhage because of an overdose of oral anticoagulants. The International Normalised Ratio (INR) was checked before and after infusion of the PCC. The mean INR in group A was 2.7 before and 1.43 after infusion of the PCC; in group B the mean INR of 6.58, before and 1.92 after drug infusion. The use of vitamin K, fresh-frozen plasma and red blood cells was also considered. During our study 22 patients died, but no adverse effects following PCC administration were recorded. In our study three-factor-PCC was found to be effective and safe in rapidly reversing the effects of OAT, although it was not always administered in accordance with international or national guidelines. The dose, time of administration and monitoring often differed from those recommended. In the light of these findings, we advocate the use of single standard protocol to guide the correct use of PCC in each hospital ward.

Guidelines on oral anticoagulation with warfarin – fourth edition

Guidelines on oral anticoagulation with warfarin – fourth edition

Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage.

Intracranial haemorrhage is a serious and potentially fatal complication of oral anticoagulant therapy. Prothrombin complex concentrates can substantially shorten the time needed to reverse the effects of oral anticoagulants. The aim of this study was to determine the efficacy and safety of a prothrombin complex concentrate for rapid reversal of oral anticoagulant therapy in patients with intracranial haemorrhage. Patients receiving oral anticoagulant therapy and suffering from acute intracranial haemorrhage were eligible for this prospective cohort study if their International Normalised Ratio (INR) was higher than or equal to 2.0. The prothrombin complex concentrate was infused at doses of 35-50 IU/kg, stratified according to the initial INR. Forty-six patients (25 males; mean age: 75 years; range 38-92 years) were enrolled. The median INR at presentation was 3.5 (range, 2-9). At 30 minutes after administration of the prothrombin complex concentrate, the median INR was 1.3 (range, 0.9-3), and the INR then declined to less than or equal to 1.5 in 75% of patients. The benefit of the prothrombin complex concentrate was maintained for a long time, since the median INR remained lower than or equal to 1.5 (median, 1.16; range, 0.9-2.2) at 96% of all post-infusion time-points up to 96 hours. No thrombotic complications or significant adverse events were observed during hospitalisation; six patients (13%) died, but none of these deaths was judged to be related to administration of the prothrombin complex concentrate. Prothrombin complex concentrates are an effective, rapid and safe treatment for the urgent reversal of oral anticoagulation in patients with intracranial haemorrhage. Broader use of prothrombin complex concentrates in this clinical setting appears to be appropriate.

Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal?

Conflicts of interest Dr M Makris has received payment for providing consultancy to and lecturing at meeting sponsored by CSL Behring and NovoNordisk.

Emergency reversal of anticoagulation and antiplatelet therapies in neurosurgical patients

Intracranial hemorrhage (ICH) is a common problem encountered by neurosurgeons. Patient outcomes are influenced by hematoma size, growth, location, and the timing of evacuation, when indicated. Patients may have abnormal coagulation due to pharmacological anticoagulation or coagulopathy due to underlying systemic disease or blood transfusions. Strategies to reestablish the integrity of the clotting cascade and platelet function assume a familiarity with these processes. As patients are increasingly treated with anticoagulants and antiplatelet agents, it is essential that the physicians who care for patients with ICH understand these pathways and recognize how they can be manipulated to restore hemostasis.

Prothrombin complex concentrate is effective for emergency anticoagulation reversal,

Prothrombin complex concentrate is effective for emergency anticoagulation reversal,

Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses.

Intracranial hemorrhage is the most feared and lethal complication of oral anticoagulation. We review the frequency, predictors, and prognosis of this most common neurological complication of oral anticoagulation. Anticoagulation to conventional intensities increases the risk of intracranial hemorrhage 7- to 10-fold, to an absolute rate of nearly 1%/y for many stroke-prone patients. Most (70%) anticoagulant-related intracranial hemorrhages are intracerebral hematomas (approximately 60% are fatal); the bulk of the remainder are subdural hematomas. Predictors of anticoagulant-related intracerebral hematoma are advanced patient age, prior ischemic stroke, hypertension, and intensity of anticoagulation. In approximately half of anticoagulated patients with intracerebral hematoma the bleeding evolves slowly over 12 to 24 hours, and emergency reversal of anticoagulation is crucial. Both patient factors and anticoagulation intensity importantly influence the rate of anticoagulation-related intracranial hemorrhage. Patient-related risk factors for this complication overlap with those for ischemic stroke. The risk/benefit equation of anticoagulation for elderly, stroke-prone patients is complex and differs from that for younger patients. The absolute rate reduction (not the relative risk reduction) of ischemic stroke by anticoagulation is the critical issue and must offset accentuation of often lethal brain hemorrhage.

Emergency reversal of anticoagulation after intracerebral hemorrhage.

Emergency reversal of anticoagulation after intracerebral hemorrhage.

Emergency reversal of anticoagulation after intracerebral hemorrhage: Fredriksson K, Norrving B, Strömblad L-G Stroke 23:972–977 Jul 1992

Emergency reversal of anticoagulation after intracerebral hemorrhage: Fredriksson K, Norrving B, Strömblad L-G Stroke 23:972–977 Jul 1992