Homogeneous low-molecular-weight heparins with reversible anticoagulant activity.

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.

Retrospective study of twenty-four patients with prolonged coagulopathy due to long-acting anti-vitamin K rodenticide poisoning.

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.

Rapid Warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate.

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.

Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?

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.

Postinjury hyperfibrinogenemia compromises efficacy of heparin-based venous thromboembolism prophylaxis.

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.

Novel thrombin and factor Xa inhibitors: challenges to reversal of their anticoagulation effects.

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.

Managing new oral anticoagulants in the intensive care unit.

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.

Rapid reversal of warfarin-associated hemorrhage in the emergency department by prothrombin complex concentrates.

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.

[Basic algorithm for Point-of-Care based hemotherapy: perioperative treatment of coagulopathic patients]. / Basisalgorithmus für "Point-of-Care" basierte Hämotherapie : Perioperative Versorgung koagulopathischer Patienten.

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.

Pharmacologic interventions for reversing the effects of oral anticoagulants.

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.

Developing a management plan for oral anticoagulant reversal.

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.