The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing.

Congenital haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked bleeding disorders. Replacement therapy has been the cornerstone of the management of haemophilia, aiming to reduce the mortality and morbidity of chronic crippling arthropathy. Frequent intravenous injections are burdensome and costly for patients, consequently with poor adherence and restricted access to therapy for many patients worldwide. Bioengineered clotting factors with enhanced pharmacokinetic profiles can reduce the burden of treatment. However, replacement therapy is associated with a risk for inhibitor development that adversely affects bleeding prevention and outcomes. Novel molecules that are subcutaneously delivered provide effective prophylaxis in the presence or absence of inhibitors, either substituting for the procoagulant function of clotting factors (eg, emicizumab) or targeting the natural inhibitors of coagulation (ie, antithrombin, tissue factor pathway inhibitor, or activated protein C). The ultimate goal of haemophilia treatment would be a phenotypical cure achievable with gene therapy, currently under late phase clinical investigation.

Alternative treatment options for pediatric hemophilia B patients with high-responding inhibitors: A thrombin generation-guided study.

Little is known about the challenging treatment of pediatric patients with hemophilia B and inhibitors due to disease rarity. We describe three patients diagnosed in childhood and followed up to 9 years. All three had allergic reactions to Factor IX, but two were later safely treated for bleeding episodes with activated prothrombin complex concentrates (APCC = FEIBA). The third was given only recombinant activated Factor VIIa. Based on ex vivo thrombin generation analysis, a new alternative treatment of combined bypassing agents was administered for bleeding episodes and several minor surgical procedures with no treatment-associated adverse events or thrombosis.

In vitro efficacy of pro- and anticoagulant strategies in compensated and acutely ill patients with cirrhosis.

BACKGROUND & AIMS: A simultaneous decline in pro- and anticoagulant drivers in patients with liver diseases results in a "rebalanced" haemostatic system, even in acutely ill patients. Nevertheless, both bleeding and thrombotic events are common. Here, we explored efficacy of pro- and antihaemostatic strategies in compensated and acutely ill cirrhotics which may be unpredictable given the profound haemostatic changes. METHODS: We tested the effects in vitro of the addition of clinically relevant doses of commonly used pro- and antihaemostatic strategies in plasma from healthy individuals (n = 30) and patients with compensated (n = 18) and acutely decompensated cirrhosis (n = 18), and acute-on-chronic liver failure (n = 10). We used thrombin generation tests and fibrin clot permeability assays to assess potency of various approaches. RESULTS: Fresh frozen plasma and recombinant factor VIIa modestly increased thrombin generation (10%-20%). Prothrombin complex concentrate increased thrombin generation two-fold in controls and 2-4-fold in patients. Clot permeability decreased after addition of fibrinogen concentrate by 51% in controls and by 50%-60% in patients. Low molecular weight heparin decreased thrombin generation by 18% in controls and by 23%-54% in patients. Similarly, dabigatran decreased thrombin generation by 33% in controls and by 47%-100% in patients. In contrast, rivaroxaban decreased thrombin generation by 55% in controls, but only by 11%-38% in patients. CONCLUSIONS: These in vitro data suggest little prohaemostatic effect of fresh frozen plasma and recombinant factor VIIa in acutely ill cirrhotics, whereas prothrombin complex concentrate and fibrinogen concentrate clearly improved haemostasis. Furthermore, our data suggest the requirement for dose adjustments of commonly used anticoagulants in these patients.

Engineering of a membrane-triggered activity switch in coagulation factor VIIa.

Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor-complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects. To exploit these properties of TF, a covalent complex between FVIIa and the soluble ectodomain of TF (sTF) was engineered by introduction of a nonperturbing cystine bridge (FVIIa Q64C-sTF G109C) in the interface. Upon coexpression, FVIIa Q64C and sTF G109C spontaneously assembled into a covalent complex with functional properties similar to the noncovalent wild-type complex. Additional introduction of a FVIIa-M306D mutation to uncouple the sTF-mediated allosteric stimulation of FVIIa provided a final complex with FVIIa-like activity in solution, while exhibiting a two to three orders-of-magnitude increase in activity relative to FVIIa upon exposure to a procoagulant membrane. In a mouse model of hemophilia A, the complex normalized hemostasis upon vascular injury at a dose of 0.3 nmol/kg compared with 300 nmol/kg for FVIIa.

Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors.

BACKGROUND: People with hemophilia A or B with inhibitors are at high risk of bleeding complications. Infusion of bypassing agents, such as recombinant activated FVII (rFVIIa) and plasma-derived activated prothrombin complex concentrate, are suggested as alternative therapies to factor VIII (haemophilia A) or IX (haemophilia B) for individuals who no longer respond to these treatments because they develop inhibitory antibodies. The ultimate goal of treatment is to preserve the individual's joints, otherwise destroyed by recurrent bleeds. OBJECTIVES: To assess the effects of bypassing agent prophylaxis to prevent bleeding in people with hemophilia A or B and inhibitors. SEARCH METHODS: We searched for relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries (16 February 2017) and bibliographic references of retrieved studies were reviewed for potential articles to be included in the review.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Coagulopathies Trials Register: 12 December 2016. SELECTION CRITERIA: We included randomized and quasi-randomized controlled studies (cross-over or parallel design) evaluating the effect of prophylaxis treatment with bypassing agents compared with on-demand treatment, or studies evaluating the effects of high-dose compared with low-dose prophylaxis in males of any age with hemophilia with inhibitors. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data and assessed the risk of bias according to standard Cochrane criteria. They assessed the quality of the evidence using the GRADE criteria. MAIN RESULTS: We included four randomized studies (duration 7 to 15 months) involving 116 males. Risk of bias was judged to be high in two studies due to the open-label study design and in one study due to attrition bias.Two studies compared on-demand treatment to prophylaxis with bypassing agents. In one study (34 males) prophylaxis significantly reduced mean overall bleeding rates, MD - 7.27 (95% CI -9.92 to -4.62) (low quality evidence), mean number of overall bleeding events per month, MD -1.10 (95% CI -1.54 to -0.66), mean number of hemarthrosis, MD -6.60 (95% CI -9.32 to -3.88) (low quality evidence) and mean number of joints that had hemarthrosis, MD -0.90 (95% CI -1.36 to -0.44). The meta-analysis did not conclusively demonstrate significant benefit of prophylaxis on health-related quality of life as measured by Haem-A-QoL score, EQ-5D total score and utility score, EQ-5D VAS and SF-36 physical summary and mental summary score (low quality evidence for all health-related quality of life analyses).The remaining two studies compared dose regimens. The results from one study (22 males) did not conclusively demonstrate benefit or harm of high-dose versus low-dose recombinant activated factor VIIa (rFVIIa) as a prophylaxis for overall bleeding rate, MD -0.82 (95% CI -2.27 to 0.63) (moderate quality evidence), target joint bleeding rate, MD -3.20 (95% CI -7.23 to 0.83) (moderate quality evidence) and serious adverse events, RR 9.00 (95% CI, 0.54 to 149.50) (moderate quality evidence).The overall quality of evidence was moderate to low due to imprecision from limited information provided by studies with small sample sizes and incomplete outcome data in one study. AUTHORS' CONCLUSIONS: The evidence suggests that prophylaxis with bypassing agents may be effective in reducing bleeding in males with hemophilia with inhibitors. However, there is a lack of evidence for the superiority of one agent over the other or for the optimum dosage regimen. Further studies are needed to evaluate the benefits and harms of prophylaxis treatment on health-related quality of life, as well as the effects of dose of bypassing agents on the outcomes.

TRUST trial: BAY 86-6150 use in haemophilia with inhibitors and assessment for immunogenicity.

INTRODUCTION: The most serious and challenging complication of haemophilia treatment is development of inhibitors to replacement factors VIII or IX. Innovative therapies currently being explored for patients with haemophilia and inhibitors include BAY 86-6150, a modified recombinant activated factor VII (FVIIa). Immunogenicity remains a substantial barrier in this endeavour. AIM: To present safety and efficacy results of the BAY 86-6150 study in patients with inhibitors and report detailed analysis of epitope mapping in a patient who developed anti-BAY 86-6150 antibodies. METHODS: Patients aged 12-62 years with moderate or severe haemophilia A or B were eligible for the phase 3 TRUST trial if they had a history of high-titre inhibitors. Four escalating doses of BAY 86-6150 (6.5, 20, 50, 90 µg kg-1 ) were planned with ≥10 patients per dose level. Bleeding episodes were treated with BAY 86-6150. Development of anti-BAY 86-6150 antibodies was considered a serious adverse event. RESULTS: TRUST was discontinued after one patient in the 6.5-µg kg-1 cohort developed anti-BAY 86-6150 neutralizing antibodies following three exposures. The anti-BAY 86-6150 antibodies cross-reacted with and neutralized wild-type FVIIa (WT-FVIIa). Post hoc epitope mapping using peripheral blood mononuclear cells from the responding patient found that none of the 14 peptides unique to BAY 86-6150 were recognized by the patient's T cells, but strong responses were detected against 2 WT-FVIIa peptides. CONCLUSION: In the single patient with haemophilia A who developed anti-BAY 86-6150 antibodies, results of T-cell epitope mapping indicated BAY 86-6150 was no more immunogenic than WT-FVIIa.

Management of Bleeding With Non-Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents.

Vitamin K antagonists are commonly used by clinicians to provide anticoagulation to patients who have or are at risk of having thrombotic events. In addition to familiarity with the dosing and monitoring of vitamin K antagonists, clinicians are accustomed to using vitamin K if there is a need to reverse the anticoagulant effect of vitamin K antagonists. There are now 4 new non-vitamin K antagonist oral anticoagulants (NOACs) that are attractive alternatives to vitamin K antagonists. Despite similar or lower rates of serious bleeding with NOACs in comparison with warfarin, there is a pressing need for strategies to manage bleeding when it does occur with NOACs and to reverse the pharmacological effect of these agents if needed. Important steps in minimizing bleeding risks with NOACs include dose adjustment of the agents in the setting of renal dysfunction and avoidance of the concomitant use of other antithrombotic agents if feasible. Laboratory measurement of the anticoagulant effect of NOACs is best accomplished with specialized assays, although some of the more widely available coagulation tests can provide information that is potentially useful to clinicians. Nonspecific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa can be used to reverse the effect of NOACs. More specific reversing agents include the approved humanized monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran, the investigational factor Xa decoy andexanet alfa, and the synthetic small molecule ciraparantag. Both andexanet and ciraparantag have been reported to reverse the effects of the anti-Xa NOACs (rivaroxaban, apixaban, and edoxaban), and a number of other anticoagulant agents in common clinical use, as well.

Entering new areas in known fields: recombinant fusion protein linking recombinant factor VIIa with recombinant albumin (rVIIa-FP) - advancing the journey.

The novel fusion protein linking recombinant factor VIIa with recombinant albumin (rVIIa-FP) is designed to extend the half-life of recombinant factor VIIa (rFVIIa) and improve the care of hemophilia A or B patients with inhibitors. Preclinical studies in various animal models have demonstrated markedly improved pharmacokinetic and pharmacodynamic properties, as well as prolonged retention in the joint tissues, of rVIIa-FP compared with a commercially available rFVIIa (NovoSeven®). A phase I study in healthy volunteers - the first study in the PROLONG-7FP program - confirmed that rVIIa-FP has a good tolerability profile in doses of up to 1,000µg/kg and has demonstrated enhanced pharmacodynamic activity relative to rFVIIa. The half-life of rVIIa-FP at the highest dose investigated in the study was 8.5hours, which represents a 3- to 4-fold half-life extension compared with rFVIIa. Encouraging results from preclinical and phase I studies have led to the initiation of clinical studies of rVIIa-FP in patients with congenital hemophilia A or B and inhibitors, and in patients with confirmed factor VII deficiency. The results from these studies are awaited with interest by clinicians and patients alike.

Elaborating European Pharmacopoeia monographs for biotherapeutic proteins using substances from a single source.

For more than twenty years, the European Pharmacopoeia (Ph. Eur.) monographs for biotherapeutic proteins have been elaborated using the multisource approach (Procedure 1), which has led to robust quality standards for many of the first-generation biotherapeutics. In 2008, the Ph. Eur. opened up the way towards an alternative mechanism for the elaboration of monographs (Procedure 4-BIO pilot phase), which is applied to substances still under patent protection, based on a close collaboration with the Innovator company, to ensure a harmonised global standard and strengthen the quality of the upcoming products. This article describes the lessons learned during the P4-BIO pilot phase and addresses the current thinking on monograph elaboration in the field of biotherapeutics. Case studies are described to illustrate the standardisation challenges associated with the complexity of biotherapeutics and of analytical procedures, as well as the approaches that help ensure expectations are met when setting monograph specifications and allow for compatibility with the development of biosimilars. Emphasis is put on monograph flexibility, notably by including tests that measure process-dependent microheterogeneity (e.g. glycosylation) in the Production section of the monograph. The European Pharmacopoeia successfully concluded the pilot phase of the P4-BIO during its 156th session on 22-23 November 2016.

Monitoring and reversal of direct oral anticoagulants.

Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.

The Real-World Treatment of Hemorrhages Associated With Dabigatran and Rivaroxaban: A Multicenter Evaluation.

PURPOSE: Adoption of the target-specific oral anticoagulants (TSOACs) has been slow; accordingly, lack of guidance for emergent reversal confounded by the need for "direct" reversal agents has contributed significantly to warfarin entrenchment in the medical community. The purpose of this analysis is to provide real-world experiences regarding the management of the hemorrhaging patient secondary to dabigatran and rivaroxaban. METHODS: Retrospective review of patients admitted with a hemorrhage secondary to dabigatran or rivaroxaban were evaluated. Descriptive statistics were utilized for analysis. RESULTS: Four hundred forty-four patients were screened for inclusion into the study; notably, 419 (94%) of the patients were excluded because the bleed was secondary to warfarin therapy. Of those included in this analysis (n = 25), gastrointestinal bleeding accounted for 21 events (84%), followed by intracranial (n = 2; 8%) and epistaxis (n = 2; 8%). Two patients (8%) expired during admission and 6 patients (24%) expired within 6 months after discharge from the hospital. Three (12%) minor bleeds, 7 (28%) major bleeds, and 15 (60%) life-threatening bleeds were identified. Minor bleeds required careful monitoring, supportive care, and cessation of anticoagulation therapy, whereas increasing severity required multiple interventions with prothrombin complex concentrate, recombinant activated factor 7, fresh frozen plasma, packed red blood cells, cryoprecipitate, and platelets. CONCLUSION: The approach to the management of bleeding events borne from TSOACs has proven to be very heterogeneous. In the midst of this observation period, these facilities developed protocols, which created a stratification of bleeds and a more regimented approach to managing them. Although bleeding is less with new agents, the creation of pathways/algorithms for the management of TSOACs and education regarding clinical decision-making may be beneficial for the expeditious and appropriate management when these events arise.

[Intracranial hemorrhage in three haemophilic adults: A severe complication of hemophilia]. / Hémorragie intracérébrale chez trois adultes hémophiles : une complication sévère de l'hémophilie.

BACKGROUND: Intracranial hemorrhage (ICH) complications are uncommon at hemophilic patients. OBSERVATIONS: We report three cases of ICH occurring in hemophilic patients. Contributing factors were identified in two patients: hemophilia severity, presence of inhibitor, hepatitis C virus infection, and high blood pressure. No contributing factor was identified in the last patient. CONCLUSION: Rapid diagnosis of ICH is crucial in hemophilic patients. A search for contributing factors, both those specific to hemophilia, and those favoring ICH in the general population, is essential to optimize therapeutic care. Specific substitutive treatment for the deficient factor is a difficult management challenge.

The old and new: PCCs, VIIa, and long-lasting clotting factors for hemophilia and other bleeding disorders.

What is the correct use of established clotting factors, prothrombin complex concentrates (PCCs), and activated factor VII in bleeding complications of trauma, surgery, and old and new oral anticoagulants? How will new clotting factors, specifically the long-acting factors, change the hemostatic management of coagulation deficiency disorders? From bench to bedside, comparative coagulation studies and clinical trials of modified clotting factors are providing insights to help guide hemostatic management of congenital and acquired bleeding disorders. Comparative thrombin-generation studies and preclinical and clinical trials suggest that PCCs and fresh-frozen plasma are effective in reversing the anticoagulant effects of warfarin, yet there are few data to guide reversal of the new oral anticoagulants dabigatran and rivaroxaban. Although coagulation studies support the use of PCCs to reverse new oral anticoagulants, correlation with clinical response is variable and clinical trials in bleeding patients are needed. For congenital bleeding disorders, exciting new technologies are emerging from the bench. Data from clinical trials of molecularly modified coagulation factors with extended half-lives suggest the possibility of fewer infusions, reduced bleeds, and better quality of life in persons with hemophilia. Preclinical studies of other novel prohemostatic approaches for hemophilia and other congenital coagulation disorders include RNA interference silencing of antithrombin, monoclonal anti-tissue factor pathway inhibitor (anti-antibody, anti-tissue factor pathway inhibitor) aptamer, bispecific anti-IXa/X antibody, and fucoidans. Understanding the comparative coagulation studies of established prohemostatic agents, the pharmacokinetics of new long-acting clotting factors, and their correlation with bleeding outcomes will provide opportunities to optimize the hemostatic management of both congenital and acquired hemostatic disorders.

Clinical transfusion practice update: haemovigilance, complications, patient blood management and national standards.

Blood transfusion is not without risk. Although the risks of HIV and hepatitis transmission have diminished, haemovigilance programs highlight that other significant transfusion hazards remain. Sepsis from bacterial contamination is the most common residual infectious hazard in developed countries, and events due to clerical error are problematic. Unnecessary transfusions should be avoided. New national guidelines on patient blood management (PBM) emphasise holistic approaches, including strategies to reduce transfusion requirements. Perioperative PBM should incorporate preoperative haemoglobin and medication optimisation, intraoperative blood conservation, and consideration of restrictive postoperative transfusion and cell-salvage techniques. When massive transfusion is required, hospitals should implement massive transfusion protocols. These protocols reduce mortality, improve communication and facilitate adequate provision of blood products. They should include multidisciplinary team involvement and guidelines for use of blood components and adjunctive agents. Although fresh frozen plasma to red blood cell and platelet to red blood cell ratios of ≥ 1 : 2 appear to reduce mortality in trauma patients who receive massive transfusion, there is insufficient evidence to recommend specific ratios. Systematic reviews have found no significant benefit of recombinant activated factor VII in critical bleeding, and an increase in thromboembolic events; specialist haematology advice is therefore recommended when considering use of this agent. The National Safety and Quality Health Service Standards address use of blood and blood products, and provide important transfusion principles for adoption by all clinicians. Storage of red cells in additive solution results in changes, known as the "storage lesion", and studies to determine the clinical effect of the age of blood at transfusion are ongoing.

Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis.

BACKGROUND: As all anticoagulants, apixaban exposes to a bleeding risk, thus an effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), and fibrinogen concentrate (Fib) to reverse apixaban in a rabbit model of bleeding and thrombosis. METHODS: After a dose-ranging study to assess the minimal amount of apixaban increasing bleeding, 63 anaesthetized rabbits were randomized into 5 groups: control (saline), apixaban (apixaban and saline), rFVIIa (apixaban and rFVIIa), PCC (apixaban and PCC) and fibrinogen (apixaban and Fib). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis detected as cyclic flow reductions (CFRs) within 20 min. A number of parameters were recorded through ear immersion bleeding time (BT), clotting times (CT), thrombelastography, and thrombin generation time (TGT). Ultimately, a hepatosplenic section was performed to evaluate as primary endpoint the blood loss in 15 min. RESULTS: Apixaban increased blood loss (11.6 ± 3 g vs. 8.3 ± 3 g for control, p < 0.0003), lengthened BT, the prothrombin time (PT), thrombelastographic CT and decreased thrombin generation. Only rFVIIa reduced BT yet failed to improve blood loss. PCC and rFVIIa both shortened the PT, CT in thrombelastographic, and lag time in TGT. Fib improved clot firmness, enhanced thrombin generation but increased bleeding. Regarding safety, neither rFVIIa, PCC, nor Fib increased CFRs. CONCLUSION: rFVIIa, PCC, and Fib failed to reverse apixaban-induced bleeding. They only improved several laboratory parameters.

Acute hypotension associated with intraoperative cell salvage using a leukocyte depletion filter during management of obstetric hemorrhage due to amniotic fluid embolism.

Amniotic fluid embolism (AFE) is a rare but catastrophic obstetric complication that can lead to profound coagulopathy and hemorrhage. The role of cell salvage and recombinant human Factor VIIa (rFVIIa) administration in such cases remains unclear. We present a case of AFE and describe our experience with the use of cell salvage and rFVIIa administration during the resuscitation. Cell salvage and transfusion through a leukocyte depletion filter was attempted after the diagnosis of AFE was made, but the attempted transfusion was immediately followed by hypotension and a worsening of hemodynamics. rFVIIa, on the contrary, was used with clinical improvement in coagulopathy and without apparent adverse thrombotic effect.

The clinical use of prothrombin complex concentrate.

BACKGROUND: Prothrombin complex concentrate (PCC) is an inactivated concentrate of factors II, IX, and X, with variable amounts of factor VII. Guidelines recommend the use of PCC in the setting of life-threatening bleeds, but little is known on the most effective dosing strategies and how the presenting international normalized ratio affects response to therapy. OBJECTIVES: This review aims to highlight available data on monitoring techniques, address shortcomings of currently available data, the reversal of life-threatening and critical bleeds with PCC, and how this product compares to other therapeutic options used in critically ill patients. DISCUSSION: PCC has been identified as a potential therapy for critically bleeding patients, but patient-specific factors, product availability, and current data should weigh the decision to use it. Most data exist regarding patients experiencing vitamin K antagonist-induced bleeding, more specifically, those with intracranial hemorrhage. PCC has also been studied in trauma-induced hemorrhage; however, it remains controversial, as its potential benefits have the abilities to become flaws in this setting. CONCLUSION: Health care professionals must remain aware of the differences in products and interpret how three- versus four-factor products may affect patients, and interpret literature accordingly. The clinician must be cognizant of how to progress when treating a bleeding patient, propose a supported dosing scheme, and address the need for appropriate factor VII supplementation. At this point, PCC cannot be recommended for first-line therapy in patients with traumatic hemorrhage, and should be reserved for refractory bleeding until more data are available.

Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban.

BACKGROUND AND PURPOSE: Rivaroxaban has recently been approved for stroke prevention in atrial fibrillation. However, lack of an effective antidote represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with rivaroxaban, and to examine the effectiveness of different hemostatic factors in preventing excess hematoma expansion. METHODS: In C57BL/6 mice receiving 10 or 30 mg/kg rivaroxaban by gastric gavage, plasma concentration, prothrombin time, and coagulation factor activities were measured repeatedly. Thirty minutes after inducing ICH by intrastriatal collagenase-injection, mice received an intravenous injection of either saline, prothrombin complex concentrate (100 U/kg), murine fresh frozen plasma (200 µL), or recombinant human Factor VIIa (1 mg/kg). ICH volume was quantified on brain cryosections and using hemoglobin spectrophotometry 24 hours later. RESULTS: Rivaroxaban in 30 mg/kg dose substantially increased the hematoma volume in ICH induced by 0.060 U collagenase. Prothrombin complex concentrate, fresh frozen plasma, or Factor VIIa prevented excess hematoma expansion caused by anticoagulation. Prevention of hematoma expansion by prothrombin complex concentrate was dose-dependent. None of the 3 agents completely corrected the prolonged prothrombin time, although they restored the activities of deficient FII and X. CONCLUSIONS: Prothrombin complex concentrate, Factor VIIa, and fresh frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with rivaroxaban. The efficacy and safety of this reversal strategy must be further evaluated in clinical studies.

Drug, devices, technologies, and techniques for blood management in minimally invasive and conventional cardiothoracic surgery: a consensus statement from the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS) 2011.

OBJECTIVE: The objectives of this consensus conference were to evaluate the evidence for the efficacy and safety of perioperative drugs, technologies, and techniques in reducing allogeneic blood transfusion for adults undergoing cardiac surgery and to develop evidence-based recommendations for comprehensive perioperative blood management in cardiac surgery, with emphasis on minimally invasive cardiac surgery. METHODS: The consensus panel short-listed the potential topics for review from a comprehensive list of potential drugs, devices, technologies, and techniques. The process of short-listing was based on the need to prioritize and focus on the areas of highest importance to surgeons, anesthesiologists, perfusionists, hematologists, and allied health care involved in the management of patients who undergo cardiac surgery whether through the conventional or minimally invasive approach. MEDLINE, Cochrane Library, and Embase databases were searched from their date of inception to May 2011, and supplemental hand searches were also performed. Detailed methodology and search strategies are outlined in each of the subsequently published systematic reviews. In general, all relevant synonyms for drugs (antifibrinolytic, aprotinin, [Latin Small Letter Open E]-aminocaproic acid, tranexamic acid [TA], desmopressin, anticoagulants, heparin, antiplatelets, anti-Xa agents, adenosine diphosphate inhibitors, acetylsalicylic acid [ASA], factor VIIa [FVIIa]), technologies (cell salvage, miniaturized cardiopulmonary bypass (CPB) circuits, biocompatible circuits, ultrafiltration), and techniques (transfusion thresholds, minimally invasive cardiac or aortic surgery) were searched and combined with terms for blood, red blood cells, fresh-frozen plasma, platelets, transfusion, and allogeneic exposure. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of each recommendation. RESULTS AND RECOMMENDATIONS: Database search identified more than 6900 articles, with 4423 full-text randomized controlled trials assessed for eligibility, and the final 125 systematic reviews and meta-analyses were used in the consensus conference. The results of the consensus conference, including the evidence-based statements and the recommendations, are outlined in the text, with references given for the relevant evidence that formed the basis for the statements and recommendations. RECOMMENDATIONS FOR ANTIFIBRINOLYTICS: The lysine analogs ?-aminocaproic acid (Amicar) and tranexamic acid (TA) reduce exposure to allogeneic blood inpatients undergoing on-pump cardiac surgery. These agents are recommended to be used routinely as part of a blood conservation strategy especially in patients at risk of undergoing onpump cardiac surgery (Class I, Level A). It is important not to exceed maximum TA total dosages (50Y100mg/kg) because of potential neurotoxicity in the elderly and open-heart procedures (Class IIb, Level C). Aprotinin is not recommended in adult cardiac surgery until further studies on its safety profile have been performed (Class III, Level A). RECOMMENDATIONS FOR TA IN OFF-PUMP CORONARY ARTERY BYPASS: Tranexamic acid may be recommended as part of a blood conservation strategy in high risk patients undergoing off-pump coronary artery bypass (OPCAB) surgery (Class I, Level A).Tranexamic acid dosing in OPCAB surgery needs further study particularly with regard to possible neurotoxicity such as seizures.In addition, the benefit-risk ratio in OPCAB needs further eludication because of the lower inherent risk for bleeding in this group (Class IIb, Level C). RECOMMENDATIONS FOR DDAVP: DDAVP can be considered for prophylaxis in coronary artery bypass grafting (CABG) surgery, in particular, for patients onASA within 7 days or prolonged CPB more than 140 minutes (Class IIa, Level A). Caution should be used with the DDAVP infusion rate to avoid significant systemic hypotension (Class I, Level A). RECOMMENDATIONS FOR TOPICAL HEMOSTATICS: The routine use of topical antifibrinolytics in cardiac surgery isnot recommended (Class IIa, Level A). Topical fibrin sealants may be considered in clinical situations where conventional approaches of surgical and medical improvement of hemostasis are not effective, that is, with bleeding problems more local than generalized, bearing in mind the blackbox warning of bovine thrombin by the US Food and Drug Administration (Class IIb, Level C).Recommendations for FVIIa:Prophylactic use of FVIIa cannot be recommended because of a significant increase in the risk of thromboembolic events and stroke (Class IIa, Level A).Factor VIIa may be considered in clinical situations where conventional approaches of surgical and pharmacologic hemostasis have failed and uncontrollable hemorrhage poses a high risk of severe and life-threatening outcomes (Class IIb, Level B). RECOMMENDATIONS FOR ERYTHROPOIETIN PLUS IRON: It is reasonable to administer erythropoietin preoperatively to increase red blood cell mass in patients who are anemic or refuse blood products (such as for Jehovah's Witness faith) or who are likely to have postoperative anemia (Class IIa, Level A). RECOMMENDATIONS FOR ANTIPLATELETS BEFORE CARDIAC SURGERY: Acetylsalicylic acid may be continued until surgery (Class IIa,Level B) For stable elective CABG procedures with no drug-elutingstent, stop clopidogrel 5 days before surgery (Class I, Level A).h For stable elective CABG procedures with drug-eluting stents less than 1 year old, consider continuing clopidogrel or heparin as abridge to surgery (Class IIb, Level C).h Direct-acting P2Y12 receptor antagonists may be a better alternative than clopidogrel in acute coronary syndrome patients undergoing CABG surgery (Class IIa, Level B). RECOMMENDATIONS FOR ANTIPLATELETS AFTER CARDIAC SURGERY: In stable CABG surgery (nonYacute coronary syndrome patients), the routine use of postoperative clopidogrel with ASAis not warranted (Class IIb, Level B). RECOMMENDATIONS FOR ACUTE NORMOVOLEMIC HEMODILUTION: Acute normovolemic hemodilution can be considered in selected patients with adequate preoperative hemoglobin to reduce post-CPB bleeding (Class IIa, Level A).The routine use of acute normovolemic hemodilution is not recommended (Class IIb, Level B). RECOMMENDATIONS FOR RETROGRADE AUTOLOGOUS PRIMING: Retrograde autologous priming is recommended as a blood conservation modality to reduce allogeneic blood transfusion for onpump cardiac surgery (Class I, Level A). RECOMMENDATIONS FOR CELL SALVAGE: Routine use of cell salvage is recommended in operations where an increased blood loss is expected (Class 1, Level A). Cell salvage should be used throughout the entire operation and not merely as a replacement for CPB cardiotomy suction (Class IIa, Level A). RECOMMENDATIONS: BIOCOMPATIBLE CPB CIRCUITS: The routine use of biocompatible coated CPB circuitry may be considered as part of a multimodal blood conservation program. However, the heterogeneity of surface-modified products, anticoagulation management, and CPB technique does not significantly impact surgical blood loss and transfusion needs (Class IIb,Level A). RECOMMENDATIONS FOR MINIATURIZED EXTRACORPOREAL CARDIOPULMONARY CIRCUIT VERSUS CONVENTIONAL EXTRACORPOREAL CARDIOPULMONARY CIRCUIT: Miniaturized extracorporeal cardiopulmonary circuit can be considered as a blood conservation technique to reduce allogeneic blood exposure (Class IIa, Level A); however, issues related to heparinization management and biocompatible coatings remain to be clarified. RECOMMENDATIONS FOR ULTRAFILTRATION (CONTINUOUS OR MODIFIED):h Ultrafiltration may be considered for blood conservation (Class IIb, Level A); however, the impact on clinically relevant outcomes remains unknown. RECOMMENDATIONS FOR PLATELET PLASMAPHERESIS:It is reasonable to recommend platelet plasmapheresis for blood management in cardiac surgery (Class IIa, Level A), although the impact on clinically relevant outcomes remains unknown. RECOMMENDATIONS FOR POINT-OF-CARE MONITORING:The evidence is too premature to recommend point-of-caretechnology for routine use because its use has not been shown to impact clinical outcome (Class IIb, Level A). RECOMMENDATIONS FOR SURGICAL TECHNIQUES FOR OPCAB, MINIMALLY INVASIVE STERNOTOMY FOR AORTIC VALVE SURGERY, MINIMALLY INVASIVE STERNOTOMY FOR MITRAL VALVE SURGERY, AND TRANSCATHETHER AORTIC VALVE IMPLANTATION: Although these minimally invasive procedures are not primarily selected for the purpose of blood management, the reduced allogeneic blood exposure should be considered in the balance of benefits and risks when selecting the appropriate surgery for patients.

[General anaesthesia and obstetric bleeding in caesarean section. One year's experience in a university hospital]. / Anestesia general y hemorragia obstétrica con transfusión en la cesárea. Experiencia durante un año en un hospital universitario.

INTRODUCTION: Obstetric haemorrhage is an important worldwide cause of morbidity and mortality. General anaesthesia for caesarean section is rarely used. Our goal is to analyse the incidence, causes and risk factors associated with general anaesthesia for caesarean section, and the prevalence of obstetric haemorrhage (HO), its risk factors and predictors of post-caesarean HO together with the use of blood in our hospital population. METHODS: A retrospective study was conducted on all caesarean section discharge reports from PACU in 2008. RESULTS: General anaesthesia was required in 12.4% of the patients. Epidural catheter failure as a cause of general anaesthesia was infrequent (2.8%) and within the recommended standards. CONCLUSIONS: The most frequent indications for caesarean section under general anaesthesia included mainly life-threatening emergencies, and the most important risk factors for general anaesthesia, including coagulation disorders, bleeding in the third trimester, foetal distress and severe pre-eclampsia. General anaesthesia is a risk factor for transfusion, as is abruptio placentae, placenta previa and pre-eclampsia.