Search

Low-molecular-weight heparins (LMWHs) are carbohydrate-based anticoagulants clinically used to treat thrombotic disorders, but impurities, structural heterogeneity or functional irreversibility can limit treatment options. We report a series of synthetic LMWHs prepared by cost-effective chemoenzymatic methods. The high activity of one defined synthetic LMWH against human factor Xa (FXa) was reversible in vitro and in vivo using protamine, demonstrating that synthetically accessible constructs can have a critical role in the next generation of LMWHs.

Second generation anticoagulant rodenticides are now the most common rat killers used in China; however, poisoning incidents are frequently reported. The authors retrospectively reviewed 24 patients with vitamin K-dependent coagulation factor deficiency caused by rodenticide poisoning in the past 2 years. The main clinical presentation was hemorrhage, although intracranial bleeding and life-threatening symptoms were not seen. All patients responded to vitamin K, the specific antidote, along with fresh frozen plasma and cryoprecipitate, although prolonged treatment was sometimes required. To avoid such incidents, rodenticide should be safely stored and protective measures used during production and application. Once poisoning has occurred, vitamin K should be administered as soon as possible along with fresh frozen plasma and cryoprecipitate.

Newer oral anticoagulants offer several advantages over traditional agents (e.g. warfarin), but they are still associated with a bleeding risk and currently there is no validated reversal treatment for them. While there is little support for the use of fresh frozen plasma, and limited data available on the effects of activated recombinant factor VII, preclinical data suggest that prothrombin complex concentrates (PCCs) may have potential in this setting. PCCs are currently used to successfully reverse warfarin-induced anticoagulation; however, clinical evidence for their use with new oral anticoagulants is lacking, with most of the available data coming from preclinical animal studies. Furthermore, there appears to be variation in the ability of different PCCs to reverse the coagulopathy induced by the new anticoagulants, and a lack of correlation between the reversal of laboratory test results and the reversal of anticoagulant-induced bleeding. Although there have been encouraging results, care must be taken in generalising findings from animal models and nonbleeding human subjects to the situation in bleeding patients. Ultimately, more evidence supporting anticoagulation reversal for new anticoagulants is needed, particularly regarding the treatment of bleeding in human patients in a clinical setting. According to the current evidence, use of PCCs may be considered a reasonable approach in dire clinical situations; however, a consensus has not yet been reached regarding PCC use or dosing, due to lack of clinical data.

Background: Venous thromboembolism (VTE) prophylaxis remains debated following trauma, and recommendations have not been established. Although hyperfibrinogenemia is a marker of proinflammatory states, it also contributes to thrombus formation. Postinjury hyperfibrinogenemia is common, but the effect of hyperfibrinogenemia on VTE prophylaxis has not been fully elucidated. Therefore, we hypothesized that heparin is less effective for VTE prophylaxis following severe injury due to hyperfibrinogenemia., Methods: In vitro studies evaluated thromboelastography (TEG) parameters in 10 healthy volunteers after the addition of fibrinogen concentrate and heparin. Data from a recent randomized controlled trial, conducted at an academic level I trauma center surgical intensive care unit, were reviewed. Critically injured patients were randomized to standard VTE prophylaxis (5,000 U low-molecular-weight heparin daily) or TEG-guided prophylaxis (up to 10,000 U low-molecular-weight heparin daily) and were followed up for 5 days. Analysis was performed to evaluate the relationship between fibrinogen levels, measures of anticoagulation, and TEG parameters., Results: In vitro studies revealed increased fibrinogen reversed the effects of heparin as measured by TEG. Fifty patients were enrolled in the clinical study with 25 in each arm. Thromboelastography parameters, fibrinogen, platelet count, and anti-Xa levels did not differ between groups despite treatment provided. Fibrinogen levels increased over the 5-day study period (597 ± 24.0 to 689.3 ± 25.0), as well as clot strength (9.8 ± 0.4 to 14.5 ± 0.6), which had a significant correlation coefficient (P < 0.01). Moreover, there was a moderate inverse correlation between fibrinogen level and the effect of heparin (RF), which was significant on study days 1 and 3, implicating hyperfibrinogenemia in heparin resistance., Conclusions: Hypercoagulability and heparin resistance are common following trauma. The preclinical and clinical relationships between fibrinogen levels and hypercoagulability implicate hyperfibrinogenemia as a potential factor in heparin resistance.

Objective: To compare the safety and effectiveness of three methods of reversing coagulopathic effects of warfarin in patients with potentially life-threatening intracranial hemorrhage., Methods: A retrospective electronic medical record review of 63 patients with warfarin-related intracranial hemorrhage between 2007 and 2010 in an integrated health care delivery system was conducted. The three methods of rapid warfarin reversal were fresh-frozen plasma (FFP), activated factor VII (FVIIa; NovoSevenRT [Novo Nordisk, Bagsværd, Denmark]), and prothrombin complex concentrate (PCC; BebulinVH [Baxter, Westlake Village, California, USA], ProfilnineSD [Grifols, North Carolina, USA]), each used adjunctively with vitamin K (Vit K, phytonadione). We determined times from reversal agent order to laboratory evidence of warfarin reversal (international normalized ratio [INR]) in the first 48 hours and compared INR rebound rates and complications in the first 48 hours., Results: Reversal with FFP took more than twice as long compared with FVIIa or PCC. To reach an INR of 1.3, mean (±SD) reversal times were 1933 ± 905 minutes for FFP, 784 ± 926 minutes for FVIIa, and 980 ± 1021 minutes for PCC (P < 0.001; P < 0.01 between FFP and FVIIa, P < 0.05 between FFP and PCC). INR rebound occurred in 0 of 31 patients for FFP, 4 of 8 for FVIIa, and 0 of 7 for PCC (P = 0.001). Complications were uncommon. FVIIa was 15 and 3.5 times as expensive as FFP and PCC, respectively., Conclusion: As an adjunct to Vit K for rapid warfarin reversal, FVIIa and PCC appear more effective than FFP. Either FVIIa or PCC are reasonable options for reversal, but FVIIa is considerably more expensive and may have greater risk of INR rebound., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Life-threatening warfarin-associated hemorrhage is common, with a high mortality. In the United States, the most commonly used therapies--fresh frozen plasma and vitamin K--are slow and unpredictable and can result in volume overload. Outside of the United States, prothrombin complex concentrates are often used instead; these pooled plasma products reverse warfarin anticoagulation in minutes rather than hours. This article reviews the literature relating to warfarin reversal with fresh frozen plasma, prothrombin complex concentrates, and recombinant factor VIIa and provides elements for a management protocol based on this literature., (Copyright © 2013 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

Purpose of Review: Warfarin has been the sole oral anticoagulant used in the management of thromboembolic disorders for over 60 years. Target-specific oral anticoagulants (TSOAs) have recently emerged as alternatives to warfarin, because they do not require laboratory monitoring. Nevertheless, with the rising use of TSOAs, there is growing concern among clinicians regarding management of bleeding in patients taking them. Unlike warfarin, there is no antidote or reversal agent for TSOAs. This review summarizes recent developments and attempts to provide a systematic approach to patients on TSOAs presenting with bleeding complications., Recent Findings: Currently, data involving clinical management of TSOAs are limited and primarily based on ex-vivo or animal models using hemostatic agents with uncertain implications in bleeding patients. There is a pressing need for randomized clinical trials evaluating the safety and efficacy of hemostatic agents., Summary: Without evidence-based guidelines for TSOA management, appropriate patient care requires an understanding of TSOA pharmacology, their effect on coagulation tests and, hence, a correct interpretation of test results, as well as a systematic approach to bleeding complications.

Warfarin has been the mainstay of oral anticoagulation for more than half a century. Within the last several years, 2 new classes of oral anticoagulants have been introduced as potential alternatives to warfarin for certain indications. The oral direct thrombin inhibitor, dabigatran, and 2 factor Xa inhibitors, rivaroxaban and apixaban, are the newest agents approved for use in the United States. These agents have been studied in various areas including stroke prophylaxis in atrial fibrillation, prevention and treatment of venous thromboembolism, and for reduction of ischemic events following acute coronary syndromes. While these agents do not require routine monitoring of international normalized ratio, these agents may be more challenging to reverse than traditional warfarin therapy. The following review will focus on describing the areas where the new oral anticoagulant agents have been studied, the basic pharmacologic characteristics of each agent, and how to appropriately manage the reversal of these agents when indicated.

Intracerebral hemorrhage (ICH) is the most devastating complication of oral anticoagulation (OAC). As the number of patients on long-term OAC is expected to rise, the proportion of intracerebral hemorrhage related to OAC (OAC-ICH) in relation to spontaneous ICH (spont-ICH) is expected to increase as well. We determined the proportion of OAC-ICH in consecutive stroke patients and explored differences between OAC-ICH and spont-ICH regarding initial volume, hematoma expansion and outcome. Our prospective study consecutively enrolled patients with supra- and infratentorial ICH. The National Institute of Health Stroke Scale Score and the modified Rankin Scale (mRS) score at baseline and after 3 months, medical history and demographic variables were recorded. All admission and follow-up CTs/MRIs were analysed regarding ICH volume using the ABC/2-method. Intraventricular hemorrhage (IVH) was quantified using the Graeb score. Within 19 months, 2,282 patients were admitted to our ER. 206 ICH patients were included. Overall, 24.8 % of all ICH were related to OAC. Compared to patients with spont-ICH, OAC-ICH patients were older (p = 0.001), more frequently had initial extension of ICH into the ventricles (p = 0.05) or isolated primary IVH (p = 0.03) and a higher Graeb score upon admission (p = 0.01). In contrast, initial ICH volume (p = 0.16) and ICH expansion (p = 0.9) in those receiving follow-up imaging (n = 152) did not differ between the two groups. After correction for age, there was a trend towards poorer outcome in OAC-ICH (p = 0.08). One-fourth of all ICH are related to OAC. Initial extension of ICH into the ventricles and primary IVH are more frequent in OAC-ICH. The rate of hematoma expansion in OAC-ICH patients is similar to non-anticoagulated ICH patients.

Background: A rapid method of reversal is required for patients on warfarin who suffer acute bleeding or require emergency surgery. Prothrombin complex concentrates (PCCs) have recently been recommended by the Canadian Blood Services for use at a fixed low dose of 1000 IU of Factor (F)IX activity. The main goal of this study was to investigate both the effectiveness and the safety of fixed low-dose PCCs., Study Design and Methods: We retrospectively reviewed charts from 103 patients who received PCCs for reversal of warfarin therapy., Results: A total of 103 patients were treated with PCC at a single fixed dose of 1000 IU of F IX activity. Fifty patients (48.5%) had a final international normalized ratio (INR) response of not more than 1.5 and an additional 45 patients (43.7%) had a final INR response between 1.6 and 2.0. However, 86 patients (83.5%) had an excellent clinical response consisting of control of bleeding without the requirement of additional measures. In a multivariable model, patients who received fresh-frozen plasma and patients who were given doses greater than 1000 IU of PCC were both identified as predictors of a poor clinical response (odds ratio [OR] 3.48, 95% confidence interval [CI] 0.76-15.89, p = 0.11; and OR 10.8, 95% CI 2.08-56.28, 95% CI, p = 0.005, respectively). There were five adverse events up to 30 days after PCC use., Conclusion: At a fixed dose of 1000 IU of F IX activity, PCC seems to be effective and safe but randomized controlled trials, specifically examining different doses of PCC, are required to confirm the above observations., (© 2012 American Association of Blood Banks.)

Prothrombin complex concentrates (PCCs) offer a means for the rapid reversal of warfarin, particularly in the setting of life-threatening bleeding. We evaluated the effectiveness and safety of a PCC-based protocol in patients with warfarin-associated intracerebral hemorrhage (ICH), subdural hematoma (SDH), or subarachnoid hemorrhage (SAH). This was a retrospective case-series review of patients treated with an institution-approved warfarin reversal protocol. Patients with intracranial hemorrhage and known warfarin use with an international normalized ratio (INR)>1.4 received fresh frozen plasma (FFP), vitamin K (phytonadione), and weight-based, 3-factor PCC (Profilnine(®) SD) dose based on the initial INR. Demographic and clinical information, the degree of and time to INR normalization, and adverse events were recorded. The thirty study patients included 19 with primary ICH, 7 with SDH, and 4 with SAH. The mean age was 72.8 (±11) years, including 11 (37%) patients ≥80years old. The median presenting INR was 2.3 (IQR 2-3.3) and post-treatment INR was 1.4 (IQR 1.3-1.5, Z score 6.4, p<0.001). Median time from PCC administration to the first follow up INR was 95 (IQR 50-140) min. No patient's INR increased by more than 0.3 over 72h. Nine patients (30%) underwent neurosurgical procedures after PCC administration and no procedure-related bleeding complication was noted. Adverse events included 3 instances of early hematoma expansion, one ischemic stroke in a patient with endocarditis on post-PCC day 1, one pulmonary embolism 5weeks after PCC treatment, and one coronary in-stent thrombosis 60days after PCC treatment. 6 patients died prior to hospital discharge of anticipated complications of their initial event, and none from identifiable thrombotic complications of PCC. A 3-factor PCC preparation (Profilnine(®) SD), administered with FFP and vitamin K to patients with acute warfarin-associated intracranial bleeding is a reasonable approach to urgent warfarin reversal. However, randomized, prospective trials are needed to verify the safety and clinical effectiveness of PCC administration in this population., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Rivaroxaban has been approved as an antithrombotic agent for prevention of venous thromboembolism with specific indications. At present no antidote is appointed and no guidelines have been formulated for the measurement of Rivaroxaban reversal., Objectives: In the present study, we have evaluated the influence of prothrombin complex concentrate (PCC) on the anticoagulant effects of Rivaroxaban as measured by prothrombin time (PT) and thrombin generation tests (TGTs)., Methods: Plasma and whole blood samples from healthy volunteers were spiked with Rivaroxaban (up to 800 μg L(-1) ) and PCC was added to these samples in concentration ranges as used clinically to reverse the effects of vitamin K antagonists. PT, endogenous thrombin potential (ETP) and calibrated automated thrombography (CAT) assays were performed with varying tissue factor (TF) concentrations., Results: Addition of PCC to Rivaroxaban-spiked samples did not result in normalization of PT and TGT lag time/T-Lag in ETP and CAT, respectively. In contrast, normalization of ETP and CAT area under the curve did occur. However, the response to PCC addition was strongly TF concentration dependent and in whole blood less PCC was required for Rivaroxaban reversal as compared with plasma., Conclusions: Prothrombin complex concentrate does not neutralize the lengthening effect on PT and TGT lag time/T-Lag of Rivaroxaban anticoagulated blood in vitro; however, total thrombin potential could be normalized. Response of the different TGTs in this respect is assay condition dependent. Therefore, prospective studies are needed to clarify which assay condition and parameter describes in vivo hemostasis best in patients on Rivaroxaban who are treated with PCC., (© 2013 International Society on Thrombosis and Haemostasis.)

During perioperative treatment of coagulopathic patients the so-called Point-of-Care (POC) analyses enable more rapidly available and more comprehensive hemostatic analyses compared to routinely performed conventional coagulation testing, such as activated partial thromboplastin time (aPTT), international normalized ratio (INR), fibrinogen concentration and platelet count. In this review article a hemotherapy algorithm is presented which is based on viscoelastic and aggregometric POC measurements. The algorithm was designed double sided and consists of a general and a special part. The general part contains boxes and fields for sociodemographic data and gives general recommendations for coagulation management and therapy specifications for particular patient collectives and presents proposals for emergency reversal of anticoagulation therapy. The special part refers to basic physiological conditions for hemostasis and asks for measurement results of clot initiation, clot firmness, clot stability and platelet function analyses. Reference values were defined for each parameter and therapeutic options are presented. In cases of persistent coagulopathy despite algorithm-conform therapy, the algorithm could be run through once again. Finally, the algorithm presents therapeutic options for an ultima ratio therapy approach.

Purpose: To describe the pharmacologic agents and strategies used for urgent reversal of warfarin and the target-specific oral anticoagulants dabigatran, rivaroxaban, and apixaban., Summary: To reverse the anticoagulant effects of warfarin in patients who are bleeding or need surgery, exogenous vitamin K (phytonadione) may be used in combination with another, shorter-acting intervention, such as fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), recombinant factor VIIa, or activated PCC (aPCC). Three-factor PCC contains factors II, IX, and X in an inactivated form, and four-factor PCC also includes factor VII in an inactivated form. No four-factor PCC products are available in the United States, but aPCC, which contains the same four factors with factor VII provided in an activated form, is available. The intervention depends on the International Normalized Ratio, presence of bleeding, and need for and timing of surgery. Research suggests that clotting factor concentrates are more effective than FFP alone for warfarin reversal. These products also may be useful for reversing the effects of target-specific oral anticoagulants, but limited efficacy and safety data are available to support their use. The risks and benefits associated with these products need to be weighed before their use for reversal of dabigatran, rivaroxaban, or apixaban. Additional clinical data are needed to clearly define the role of concentrated clotting factor products in reversal and to determine the optimal clotting factor concentrate product and dose for urgent reversal of oral anticoagulation., Conclusion: Phytonadione and clotting factor concentrates appear to have a role for reversal of warfarin, and limited evidence suggests that clotting factor concentrates could have a role in reversal of target-specific oral anticoagulants in an emergency situation.

Purpose: To describe a process for prompt evaluation and management- including reversal of the effects of warfarin and target-specific oral anticoagulants-of patients with or at high risk for bleeding during oral anticoagulant therapy or when such therapy is interrupted for an urgent invasive procedure or surgery., Summary: The use of pharmacologic interventions for anticoagulant reversal may depend on the measured level of anticoagulation, time since the last anticoagulant dose, target level of coagulation, reliability of laboratory tests of coagulation, severity of or risk for bleeding, the agents' mechanism of action and pharmacokinetics, and pharmacodynamics of the reversal agent. The patient's age, weight, renal function, comorbid conditions, and other drug therapy, as well as the risk for thromboembolism and other adverse effects of the reversal therapies, also enter into therapeutic decisions. Hemodialysis may be used to remove the direct thrombin (factor IIa) inhibitor dabigatran and reverse its anticoagulant effects. Limited experience with clotting factor concentrates suggests that activated prothrombin complex concentrate may be useful for reversing the anticoagulant effects of dabigatran. The activity of oral factor Xa inhibitors (i.e., rivaroxaban and apixaban) is higher up the common pathway of the coagulation cascade and thus may be easier to reverse than that of direct thrombin inhibitors. Additional clinical experience is needed to identify the optimal reversal agents, dosage, and impact on thrombosis or bleeding outcomes for both classes of agents., Conclusion: A comprehensive plan individualized to each agent should be developed to promptly reverse the effects of oral anticoagulants and optimize outcomes in patients with bleeding or an urgent need for surgery.

Background: The rapid reversal of the effects of vitamin K antagonists is often required in cases of emergency surgery and life-threatening bleeding, or during bleeding associated with high morbidity and mortality such as intracranial haemorrhage. Increasingly, four-factor prothrombin complex concentrates (PCCs) containing high and well-balanced concentrations of vitamin K-dependent coagulation factors are recommended for emergency oral anticoagulation reversal. Both the safety and efficacy of such products are currently in focus, and their administration is now expanding into the critical care setting for the treatment of life-threatening bleeding and coagulopathy resulting either perioperatively or in cases of acute trauma., Methods: After 15 yr of clinical use, findings of a pharmacovigilance report (February 1996-March 2012) relating to the four-factor PCC Beriplex P/N (CSL Behring, Marburg, Germany) were analysed and are presented here. Furthermore, a review of the literature with regard to the efficacy and safety of four-factor PCCs was performed., Results: Since receiving marketing authorization (February 21, 1996), ~647 250 standard applications of Beriplex P/N have taken place. During this time, 21 thromboembolic events judged to be possibly related to Beriplex P/N administration have been reported, while no incidences of viral transmission or heparin-induced thrombocytopenia were documented. The low risk of thromboembolic events reported during the observation period (one in ~31 000) is in line with the incidence observed with other four-factor PCCs., Conclusions: In general, four-factor PCCs have proven to be well tolerated and highly effective in the rapid reversal of vitamin K antagonists.

Novel oral anticoagulants (NOACs) have been associated with multiple safety benefits compared with vitamin K antagonists in patients with diseases at high thromboembolic potential, including nonvalvular atrial fibrillation. Although these agents have several distinct advantages, they are limited by the lack of a proven antidote, which may represent a major concern in case of life-threatening bleeding. Several different drugs and compounds are currently under investigation as reversing agents of NOACs. This article provides an overview of potential NOACs antidotes, including recent patents of emerging compounds.

Patients on warfarin who have traumatic intracranial haemorrhage have a high mortality. The procoagulant recombinant factor VIIa (rFVIIa) is widely used off-label to treat intracranial haemorrhaging in patients taking warfarin to try to improve these adverse outcomes, but its effectiveness is unknown. In this study, medical records from 2002 to 2010 were reviewed for 27 warfarin patients who received rFVIIa for their traumatic intracranial haemorrhage and were compared with a matched control group of 27 warfarin patients who did not receive rFVIIa. The two groups were matched for sex, age and Injury Severity Score. The rFVIIa patients had 33.3% mortality compared with the 37% for the control patients, but this was not a statistically significant difference. There was also no significant difference in plasma unit use between the groups. However, the rFVIIa group had a significantly higher number of subdural haemorrhages, which carry a better prognosis. The initial international normalized ratios (INRs) of the rFVIIa patients were higher, and the decrease of INR was more pronounced than in the control patients. From the data, it appears that although the INRs of rFVIIa patients did improve compared with the control group, there was no reduction in plasma use or mortality.

Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.

Objective: Earlier detection of coagulopathy in pediatric cardiac surgery patients., Aim: To determine whether thromboelastometry (TEM) analysis before weaning from cardiopulmonary bypass (CPB) and hemoconcentration is predictive of post-CPB results and whether analysis of clot firmness already after 10 min yields reliable results., Background: Cardiac surgery with CPB induces a coagulopathy that may contribute to postoperative complications. Earlier detection increases the possibility of initiating countermeasures. METHODS/MATERIAL: Fifty-six pediatric cardiac surgery patients were included in a prospective observational study. HEPTEM and FIBTEM clotting time (CT), clot formation time (CFT), and clot firmness after 10 min (A10) and at maximum (MCF) were analyzed during CPB and after CPB and ultrafiltration with modified rotational thromboelastometry (ROTEM). The analyses were compared, and correlations and differences were calculated., Results: Hemoconcentration with modified ultrafiltration increased hematocrit from 28 ± 3 to 37 ± 4% (P < 0.001). Correlation coefficients of the TEM variables during and after CPB ranged from 0.61 to 0.82 (all P < 0.001). HEPTEM-CT and HEPTEM-MCF differed significantly but the differences were marginal. Both HEPTEM and FIBTEM A10 measurements during CPB were significantly less than MCF (P < 0.001 for both), but the correlations were highly significant (HEPTEM: r = 0.95, P < 0.001; FIBTEM: r = 0.96, P < 0.001), and the differences were predictable, with narrow confidence intervals (HEPTEM: -8.2 mm (-8.9 to -7.5); FIBTEM: -0.5 mm (-0.7 to -0.3)., Conclusion: The results suggest that intraoperative TEM analyses can be accelerated by analyzing HEPTEM/FIBTEM on CPB before hemoconcentration and by analyzing clot firmness already after 10 min., (© 2013 Blackwell Publishing Ltd.)

Anticoagulants can complicate the approach to the management of patients undergoing operative interventions. We review new anticoagulants that have been introduced recently to the market or that are undergoing investigations for treatment of nonvalvular atrial fibrillation and venous thromboembolism prophylaxis: Dabigatran, rivaroxaban, apixiban, and edoxaban., (Copyright © 2013 Mosby, Inc. All rights reserved.)

There are a growing number of new anticoagulants used as an alternative to warfarin. Surgeons will be confronted with an increasing number of patients who may be on these outpatient medications and must be familiar with their management strategies. The purpose of this review is to examine the mechanisms, monitoring and therapeutic reversal of the non-warfarin antithrombotic agents now so frequently confronting the acute care surgeon., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Reversal of warfarin with plasma accounts for a large amount of fresh-frozen plasma transfused in the United States. The use of vitamin K is an alternate strategy., Study Design and Methods: Records of vitamin K prescriptions for warfarin reversal were examined and recipients identified where data were available on dosage, route of administration (oral [PO] and intravenous [IV]) and the availability of both pre- and postadministration international normalized ratio(s) (INRs)., Results: A total of 135 administration events were evaluated: 81 PO and 54 IV. The median (range) preadministration INRs were 5.8 (1.9-16.5) versus 5.0 (1.4-16.5; p=0.61) and the median (range) for the postadministration INRs were 2.4 (1.0-10.4) and 2.1 (1.2-8.2; p<0.01) for the PO and IV routes, respectively. The median (range) doses were 2.5(1-10) and 2.0(1-10) mg for PO and IV, respectively (p<0.01). A total of 44% of the IV vitamin K group achieved an INR of 2 or less within 12 hours versus 14% for the PO route (p<0.01). In multilinear regression the preadministration INR (r=0.14, p<0.01) and time after administration (r=-0.05, p<0.01) were independent variables influencing the postadministration INR but the dose administered (r=0.09, p=0.07) was not., Conclusion: Vitamin K needs to be given IV if urgent partial correction (<12 hr) of warfarin is required. No influence of dose administered in the range 1 to 10 mg on the postadministration INR was observed., (© 2012 American Association of Blood Banks.)

Introduction: The usefulness of anticoagulation in patients with atrial fibrillation (AF) is well known. However, the inherent limitations of vitamin K antagonists (VKAs) have made the development of new oral anticoagulants necessary. Drugs directed against thrombin or the factor Xa are currently available., Areas Covered: These molecules, being administered at fixed doses and not requiring laboratory monitoring, overcome one crucial problem associated with the use of VKAs. However, data about the bleeding risk related to the use of these molecules should be further analyzed., Expert Opinion: The efficacy of direct anticoagulants (DACs) in AF-related stroke prevention has been considered the primary outcome in all Phase III published trials. On the other hand, the reduction of the bleeding risk is an important goal achieved by the DACs as compared with VKAs. Besides data deriving from randomized trials, when talking about new drugs, the need of evidences from the 'everyday clinical practice' are often requested. The aim of this literature revision is to report and analyze data from specific subgroups about which little is known. In particular, information about the use of DACs in oncologic patients, in patients receiving concomitant antiplatelet drugs and in the perioperative period is currently lacking. The parallel evaluation of all these data may lead to the identification of clinical and demographical criteria to choose when to switch to DACs.

Background: The rapid reversal of warfarin in the setting of traumatic brain injury (TBI) has been associated with improved outcomes. Until now, remote reversal of hypocoagulable states has not been possible in the prehospital environment. This manuscript describes the development and analysis of a prehospital plasma transfusion protocol to reverse warfarin at the earliest possible moment after TBI., Study Design and Methods: A retrospective review of all TBI patients receiving plasma transfusion(s) in the prehospital environment for warfarin reversal between February 2009 and September 2010 was conducted. Thawed plasma was carried on every air ambulance flight centered at the main campus., Results: A total of 2836 flights carried over 2500 units of thawed plasma throughout the study period. During this time, 16 patients received prehospital plasma resuscitation, five of who were on warfarin with a concurrent TBI. The median Injury Severity Score was 17 (8.5-27.5) with a median Glasgow Coma Score of 13 (8-15) and a mortality rate of 40%. A median of 2 (1.5-2.0) units of thawed plasma and 0 (0-0) units of RBCs were transfused en route. The pretransfusion point-of-care international normalized ratio improved from 3.1 (2.3-4.0) to 1.9 (1.3-3.6) upon trauma center admission (serum sample). One hundred percent of the transported, but unused, thawed plasma underwent subsequent transfusion prior to expiration., Conclusions: Remote prehospital plasma transfusions effectively reverse anticoagulation secondary to warfarin administration in TBI patients. It is feasible to transfuse thawed plasma in the prehospital setting via remote damage control techniques without increasing waste. Prospective studies are needed to determine if this practice can improve outcomes in this population., (© 2013 American Association of Blood Banks.)

Introduction: Prothrombin complex concentrates are used for rapid reversal of vitamin K antagonists in patients with bleeding or those requiring surgery or invasive procedures. Current guidelines suggest 4-factor products are preferred over 3-factor prothrombin complex concentrates., Materials and Methods: We performed a systematic review comparing the effectiveness of 3-factor to 4-factor prothrombin complex concentrates in normalizing the international normalized ratio to ≤ 1.5 in patients with acquired coagulopathy due to vitamin K antagonist use. Studies reporting administration of prothrombin complex concentrates for emergent reversal of vitamin K antagonists that included results of baseline prothrombin time/international normalized ratio and follow-up testing within 60 minutes of prothrombin complex concentrates administration were included., Results: A total of 18 studies were included representing 654 patients. The most common indications for prothrombin complex concentrate were intracerebral hemorrhage, urgent surgery or invasive procedure, and gastrointestinal bleeding. Baseline international normalized ratio values ranged from 3.3-5.1 in the 3-factor group and from 2.3 to greater than 20 in the 4-factor group. The international normalized ratio repeated within one hour of prothrombin complex concentrates administration ranged from 1.2-1.9 in the 3-factor group and 1.0-1.9 in the 4-factor group. International normalized ratio decreased to ≤ 1.5 within one hour after prothrombin complex concentrates administration in 6 of 9 studies in the 3-factor group, and 12 of 13 studies in the 4-factor group., Conclusion: More reliable correction of the international normalized ratio was seen with 4-factor compared to 3-factor prothrombin complex concentrates which may have clinical implications since 4-factor products are unavailable in some countries., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Vitamin K is commonly used for reversal of anticoagulation of warfarin. However, the optimal dose and route of vitamin K that does not increase the duration of bridging therapy is unknown., Objective: To determine factors influencing the extent and rate of INR reversal with vitamin K in the acute/critical care setting., Methods: This was a chart review of 400 patients who received vitamin K for reversal of warfarin effects between February 2008 and November 2010. Data collected included international normalized ratios (INRs) 12 hours, 24 hours, and 48 hours prior to vitamin K administration; intravenous or oral vitamin K dose; and whether or not fresh frozen plasma (FFP) was administered., Results: Intravenous vitamin K reduced INR more rapidly than oral vitamin K (5.09, 1.91, 1.54, and 1.41 vs 5.67, 2.90, 2.14, and 1.58) at baseline, 12, 24, and 48 hours, respectively. The dose of vitamin K (p < 0.001), route of administration (p < 0.001), and baseline INR (p < 0.001) influenced subsequent INR values. The INR reduction was similar for intravenous vitamin K doses 2 mg or greater. Home warfarin dose did not affect INR responses to intravenous (p = 0.27) or oral vitamin K (p = 0.98). FFP did not influence INR values at 48 hours. Although longer anticoagulation bridge therapy seemed to be associated with higher vitamin K doses, the incidence (p = 0.63) and duration (p = 0.61) were not significant., Conclusions: Vitamin K dose, route, and initial INR influence subsequent INR values. INR reduction is similar for intravenous vitamin K doses of 2 mg or greater. Preadministration of FFP does not alter INR values at 48 hours or more after vitamin K administration.

Pleiotrophin, also known as heparin affin regulatory peptide (HARP), is a growth factor expressed in various tissues and cell lines. In this work, HARP was tested for its capacity to modulate the anticoagulant activity of heparin and heparan sulphate mimetics (OTR4120). We used both in vitro and in vivo assays. HARP was found to be differently effective for neutralization of the anticoagulant activity of the mimetic heparan sulphate (OTR4120) and heparin in purified system and human plasma. HARP was shown to compete with both antithrombin and thrombin for binding to heparin and to OTR4120, respectively. In the presence of OTR4120, the V(max) was constant and the calculated maximum velocity was 1.56 U/min; the thrombin Km value (0.011 nM) was affected by HARP concentrations. The Km (HARP) value was 0.085 nM, which is consistent with high affinity of HARP to OTR4120. Under the same conditions, initial velocity patterns for antithrombin-heparin were determined in the presence or in the absence of HARP. The antithrombin value Km (0.022 nM) was affected by HARP (0.077 nM). HARP exhibits efficacy equivalent to or greater than protamine. Interestingly, intraperitoneally administered HARP decreased the anticoagulant activity of heparin and of OTR4120 in mice. Taken together, these data provide the first evidence for a physiological role of HARP in the modulation of anticoagulant activity of heparin and heparin-like material., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)

Background: 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., Methods: 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., Results: 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., Conclusion: Prothrombin complex may be used safely and effectively to reverse emergently anticoagulation in geriatric trauma patients., (Copyright © 2012 Mosby, Inc. All rights reserved.)

To date, clinical studies show that the incidence of spontaneous bleeding with new direct oral anticoagulants (DOAs) is comparable to that of established anticoagulants. However, unlike vitamin K antagonists, there are currently no clinically available antidotes or approved reversal agents for new DOAs. Restoring normal coagulation is important in many cases, such as emergency surgeries, serious bleedings, or anticoagulant overdosing. Attempts have been made to restore normal coagulation after treatment with new DOAs using compounds such as recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), or FEIBA (factor eight inhibitor bypassing activity). Limited pre-clinical data and even less clinical evidence are available on the usefulness of these methods in restoring normal coagulation for the emergency management of critical bleeding episodes. Evaluating the utility of DOAs is further complicated by the fact that it is unknown how predictive established test systems are of the bleeding risks. Clinical practice requires further evaluation of the emergency management options for the new DOAs to define the agents and the doses that are most useful. Furthermore, patients receiving long-term treatment with a DOA are likely to undergo elective surgery at some point, and there is lack of evidence regarding perioperative treatment regimens under such conditions. This review summarises potential bleeding management options and available data on the new DOAs.