Search

Purpose: Hemophilia B is a bleeding disorder, caused by a factor IX (FIX) deficiency. Recently, FIX concentrates with extended half-life (EHL) have become available. Prophylactic dosing of EHL-FIX concentrates can be optimized by assessment of individual pharmacokinetic (PK) parameters. To determine these parameters, limited sampling strategies (LSSs) may be applied. The study aims to establish adequate LSSs for estimating individual PK parameters of EHL-FIX concentrates using in silico evaluation., Methods: Monte Carlo simulations were performed to obtain FIX activity versus time profiles using published population PK models for N9-GP (Refixia), rFIXFc (Alprolix), and rIX-FP (Idelvion). Fourteen LSSs, containing three or four samples taken within 8 days after administration, were formulated. Bayesian analysis was applied to obtain estimates for clearance (CL), half-life (t 1/2 ), time to 1% (Time 1% ), and calculated weekly dose (Dose 1% ). Bias and precision of these estimates were assessed to determine which LSS was adequate., Results: For all PK parameters of N9-GP, rFIXFc and rIX-FP bias was generally acceptable (range: -5% to 5%). For N9-GP, precision of all parameters for all LSSs was acceptable (< 25%). For rFIXFc, precision was acceptable for CL and Time 1% , except for t 1/2 (range: 27.1% to 44.7%) and Dose 1% (range: 12% to 29.4%). For rIX-FP, all LSSs showed acceptable bias and precision, except for Dose 1% using LSS with the last sample taken on day 3 (LSS 6 and 10)., Conclusion: Best performing LSSs were LSS with samples taken at days 1, 5, 7, and 8 (N9-GP and rFIXFc) and at days 1, 4, 6, and 8 (rIX-FP), respectively., (© 2021. The Author(s).)

Objective: The management of surgeries in patients with hemophilia is  complex and requires adequate clotting factor adjustment to avoid bleeding  complications and excessive factor consumption. The aim of this systematic  review is to analyze the pharmacokinetic studies published on surgery in  hemophilic patients, the methodologies used, the main pharmacokinetic covariates applied, and the recommendations made by clinical guidelines., Method: A structured search was performed in Pubmed, the Cochrane Library,  and the Database of Abstracts of Reviews of Effects using the search terms  hemophilia (or haemophilia), surgery and pharmacokinetics (or PK). No date or  language limits were established. Results: The search yielded 186 results, from which 34 articles were selected.  Many of these analyzed the use of continuous infusions with the aim of  achieving stable factor VIII or IX levels and reducing overall factor  consumption. However, continuous infusions have fallen into disuse. For  decades, clinical guidelines have recommended the performance of comprehensive pharmacokinetic studies prior to surgery (9-11 samples). The clearance rate obtained is used to adjust the presurgical factor  dose (or the infusion rate in case of continuous perfusion). Another approach is the use of population pharmacokinetic models, which allow adjustments to  be made based on a more limited number of samples. However, the validity of  these presurgical pharmacokinetic estimates ceases as soon as the surgical  procedure is initiated, making it necessary to adjust the dose based on periodic  peak and trough levels. In addition, depending on the  type of  surgery, clinical guidelines recommend maintaining factor VIII and IX levels  above specific thresholds for certain periods of time, which makes it essential  to use pharmacokinetics during the pre- and post-surgical process. In recent  years, specific factor VIII and factor IX pharmacokinetic population models  have been developed for surgery. The main covariates of these population  pharmacokinetic models are age, blood type, and type of surgery for factor  VIII; and age and body weight for factor IX., Conclusions: Pharmacokinetic estimation could allow individual and standardized intraoperative dose adjustments to be conducted in patients with hemophilia. The development of specific population  pharmacokinetic models for surgery, including those based on extended half- life factors, will allow an optimization of current treatments, potentially  reducing factor consumption and hospital stays., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL -1 ) and some patients with moderate hemophilia (0.01-0.05 IU mL -1 ) administer clotting factor concentrates prophylactically. Desmopressin (D-amino D-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or D-amino D-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.

Background: Clinical experience with using activated prothrombin complex concentrates (aPCCs) to reverse the effects of factor Xa inhibitors is limited., Objectives: Our objective was to assess the achievement of effective clinical hemostasis using aPCC in patients on chronic apixaban or rivaroxaban therapy presenting with major bleeding in whom a reversal agent is warranted. We also assessed the safety of the drug., Methods: A retrospective medical records review was conducted at a tertiary referral medical center in the USA. Patients presenting with major bleeding while receiving apixaban or rivaroxaban and treated with aPCC were included. Clinical hemostasis was assessed using International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria., Results: A total of 35 patients were included in the study. The most common site of bleeding was intracerebral hemorrhage (ICH) (n = 18 [51.4%]), followed by gastrointestinal bleed (n = 10 [28.6%]). Clinical hemostasis was achieved in 24 (68.6%) patients; 11 patients (31.4%) did not achieve clinical hemostasis; nine of these patients had ICH. Seven of the patients who did not achieve hemostasis died during hospitalization. Three (8.6%) patients experienced thromboembolic events during hospitalization. In total, 21 (60%) patients were receiving concomitant medications that interact with anti-factor Xa inhibitors and can increase the risk of bleeding., Conclusions: Our study suggests that aPCC could be an option in patients with major bleeding associated with apixaban or rivaroxaban. It may be an alternative for patients who need anticoagulation reversal if the specific antidote, andexanet alfa, is unavailable.

Over the past several years, novel modified clotting factor concentrates (CFCs) have been introduced into practice and are now widely prescribed in the countries where they are licensed. These products allow for less frequent infusions of CFC, thereby providing improved convenience and/or higher trough levels. They have been extensively studied for prophylaxis, episodic treatment of bleeding and for surgical prophylaxis. One issue that has emerged regarding the clinical application of these products revolves around the measurement of infused CFC in the clinical coagulation laboratory. Recent studies have demonstrated significant problems with the measurement of correct FVIII/IX levels following infusion of novel CF VIII/IX concentrates. The source of this problem appears to be related to the tremendous variability of the APTT reagents that are used in the one-stage clotting assay, the most commonly used assay for determining factor levels. More specifically, the issue is related to the type of activator used in the reagents. Depending on the combination of the CFC and the APTT activator, the observed results may be either under- or overestimated to degrees that would be clinically relevant. Recommendations based on a review of published information regarding the potential for incorrect measurements of factor VIII/IX levels following infusion of recently developed, novel factor VIII/IX CFCs are presented for the clinician to use in clinical practice., (© 2019 International Society on Thrombosis and Haemostasis.)

Hemophilic arthropathy from joint bleeding remains a complication with major morbidity in the increasingly aging patients with hemophilia. Prophylactic clotting factor infusions, based on pharmacokinetic dosing to reduce bleeding rates, are being explored more and more. However, there is little evidence on the benefits of pharmacokinetic dosing in direct association with bleeding events. Here, we prospectively followed a cohort of adult patients with hemophilia A and B (n = 26) and arthropathic joints on various clotting factor products over a period of 2 years with clinical and radiographic joint health assessments, frequent joint ultrasound, and pharmacokinetic studies. Joint bleeds and synovitis with synovial vascularity changes were objectively diagnosed by musculoskeletal ultrasound and power Doppler and analyzed in relation to pharmacokinetic, joint- and patient-specific parameters. Results revealed that, contrary to common beliefs, bleeding episodes were not readily explained by pharmacokinetic features, as they were not associated with more time spent below certain clotting factor thresholds. Joint bleeding was found to be associated with prominent vascularity changes, suggesting that vascular remodeling and leakiness may contribute to joint bleeding that cannot be prevented by clotting factor replacement alone.

Platelets and the coagulation cascade play key roles in initiation, amplification, and perpetuation of acute coronary syndromes (ACS). In the past few years, there has been great progress in ACS antithrombotic treatment with the introduction of novel anticoagulants (fondaparinux and bivalirudin), more potent P2Y 12 inhibitors (prasugrel and ticagrelor) and protease-activated receptor antagonists (vorapaxar). Nonetheless, patients with ACS frequently have recurrent ischemic events despite the use of currently recommended dual antiplatelet therapy, revascularization procedures as appropriate, and other evidence-based secondary preventive measures. This is the rationale beyond intensification of antiplatelet therapy. However, the major downside of intensive antithrombotic therapy is bleeding. When treating ACS patients, clinicians should find the adequate balance between the reduction of thrombotic events by effective drug treatment and the induction of bleeding that is linked to the use of potent or multiple antithrombotic agents. Numerous antithrombotic cocktails including oral anticoagulants with or without aspirin have been tested in large clinical trials with the goal of further reduction of ischemia and bleeding risk. The aim of this review is to discuss clinical outcomes resulting from inhibition of multiple coagulative pathways in patients with ACS in light of evidence from large randomized controlled clinical trials.

Extended half-life proteins (EHL) are increasingly used in clinical practice, but there is no standardized approach to sampling, interpretation and implementation of pharmacokinetics (PK) data to maximize treatment benefit. The goal of EHL treatment is to attain a trough level sufficient to protect against spontaneous bleeds and reduce infusion frequency and limitations on individual activity and lifestyle. Performing classical PK assessments requires multiple blood samples, which is burdensome for patients and providers. Herein we review a population pharmacokinetic (popPK) approach to estimate individual PK parameters to transition patients from standard half-life (SHL) to EHL concentrates. We propose that a minimum of two to four post-infusion samples is sufficient to estimate individual PK profiles, with sufficient certainty to maintain factor levels above 1% and achieve bleed-free lifestyles. We also survey current PK use in patients transitioning to EHL, review key PK parameters and popPK models, and recommend an approach to using PK in patients initiating or switching to EHL., (© 2018 International Society on Thrombosis and Haemostasis.)

Bypassing therapy is essential for the haemostatic management of patients with haemophilia A with inhibitor (PWHA-inh), but the therapeutic effects are inconsistent. We previously reported that activated prothrombin complex concentrates (aPCC) activated factor (F)VIIIin vitro, and was mediated mainly by the activated FVII (FVIIa) contained in aPCC. We have extended those studies to assess global coagulation in whole blood from 18 PWHA-inh in the co-presence of aPCC and FVIII using Ca 2+ -triggered rotational thromboelastometry. The clot times (CTs) in the presence of both aPCC (0·05 iu/ml) and recombinant (r)FVIII (1 iu/ml) ex vivo were shortened compared to the aPCC alone (P < 0·01). These enhancing effects of rFVIII were observed, irrespective of recognizing inhibitor epitopes; however, the clot formation time and 'α'-angle were not significantly different. In samples from 7 PWHA-inh post-infusion of aPCC (70-80 iu/kg), only the CTs were shortened in the presence of rFVIIIex vivo compared to its absence (P < 0·05), indicating that the enhanced activity centred on the initiation phase of coagulation. Furthermore, experiments in the co-presence of rFVIIa and rFVIII demonstrated that FVIII accelerated only the CTs. We concluded that FVIII/FVIIa-related coagulation mechanism enhanced global haemostatic function by the co-presence of bypassing agents and FVIII in PWHA-inh., (© 2018 John Wiley & Sons Ltd.)

Prevention and treatment of bleeding in hemophilia requires that plasma clotting factor activity of the replaced factor exceeds a defined target level. Most clinical decisions in hemophilia are based on implicit or explicit application of pharmacokinetic measures. The large interindividual variability in pharmacokinetics of factor concentrates suggests that relying on the average pharmacokinetic characteristics of factor concentrates would not allow optimizing the treatment of individual patients; for example, adjusting the frequency of infusions and targeting a specific clotting factor activity level on a case-by-case basis. However, individual pharmacokinetic profiles are seldom assessed as part of routine clinical care. Population pharmacokinetics provide options for precise and convenient characterization of pharmacokinetics characteristics of factor concentrates, simplified individual pharmacokinetic profiling, and individualized dosing. Population pharmacokinetics allow for the incorporation of determinants of interpatient variability and reduces the need for extensive postinfusion plasma sampling. Barriers to the implementation of population pharmacokinetics are the need for concentrate-specific pharmacokinetic models, Bayesian calculation power, and specific expertise for production, validation, and appraisal of forecasted estimates. Population pharmacokinetics provide an important theoretical and practical contribution to tailoring the treatment of hemophilia. The need remains for prospective exploration of the clinical impact of tailoring hemophilia treatment based on individual pharmacokinetics, and for the systematic validation of existing software solutions and concentrate-specific models., Competing Interests: Conflict-of-interest disclosure: The author declares no competing financial interests., (© 2016 by The American Society of Hematology. All rights reserved.)

The prophylactic administration of factor IX (FIX) is considered the most effective treatment for haemophilia B. The inter-individual variability and complexity of the pharmacokinetics (PK) of FIX, and the rarity of the disease have hampered identification of an optimal treatment regimens. The recent introduction of extended half-life recombinant FIX molecules (EHL-rFIX), has prompted a thorough reassessment of the clinical efficacy, PK and pharmacodynamics of plasma-derived and recombinant FIX. First, using longer sampling times and multi-compartmental PK models has led to more precise (and favourable) PK for FIX than was appreciated in the past. Second, investigating the distribution of FIX in the body beyond the vascular space (which is implied by its complex kinetics) has opened a new research field on the role for extravascular FIX. Third, measuring plasma levels of EHL-rFIX has shown that different aPTT reagents have different accuracy in measuring different FIX molecules. How will this new knowledge reflect on clinical practice? Clinical decision making in haemophilia B requires some caution and expertise. First, comparisons between different FIX molecules must be assessed taking into consideration the comparability of the populations studied and the PK models used. Second, individual PK estimates must rely on multi-compartmental models, and would benefit from adopting a population PK approach. Optimal sampling times need to be adapted to the prolonged half-life of the new EHL FIX products. Finally, costs considerations may apply, which is beyond the scope of this manuscript but might be deeply connected with the PK considerations discussed in this communication.

Bleeding complications are a common concern with the use of anticoagulant agents. In many situations, reversing of neutralizing their effects may be warranted. Prothrombin complex concentrate replaces coagulation factors lowered by warfarin, as does fresh frozen plasma, but in a more concentrated form. Protamine negates the effect of heparin and combines chemically with heparin molecules to form an inactive salt. It also partially reverses the effects of low-molecular-weight heparin. Recombinant activated factor VII is a nonspecific procoagulant that activates the extrinsic clotting pathway, resulting in thrombin generation, but does not directly neutralize the activity of any of the new oral anticoagulants., (Published by Elsevier Inc.)

Background: Real-world studies of the emergency reversal of warfarin using 4-factor prothrombin complex concentrate (PCC) report unwarranted delays. The delay to receiving PCC was ≥ 8 h in 46·7% of patients with warfarin-associated bleeding (PWAB) treated with a variable PCC dosing protocol in our retrospective audit., Objective: To report the impact of a simplified PCC dosing protocol on the interval to reversal of anticoagulation., Methods: We developed a PCC dosing protocol standardising the initial PCC dose and simplifying dosing calculations. Study end points were the proportion of PWAB achieving international normalised ratio (INR) ≤1·5 and treated within 8 h of presentation, respectively., Results: Of 17, 15 (88·2%) PWABs achieved a post-treatment INR ≤ 1·5; 14 of 17 (82·4%) PWABs were reversed within 8 h. Median intervals between triage and PCC request and PCC request and start of infusion (administration interval) were 126 min (range 39-520) and 30 min (range 5-100), respectively. Compared with the retrospective cohort, RAPID is associated with an improved administration interval (mean 37·7 vs 76 min, P = 0·031) and the proportion of PWABs treated within 30 min (58·8 vs 6·7%, P = 0·009)., Conclusion: The RAPID protocol reduces unwarranted delays without compromising efficacy., (© 2016 British Blood Transfusion Society.)

Management of hemophilia has evolved significantly in the last century-from recognition of the causative mechanism in the 1950s to commercially available clotting factor concentrates in the 1960s. Availability of lyophilized concentrates in the 1970s set the stage for home-based therapy, followed by introduction of virally attenuated plasma-derived, and then recombinant factor concentrates in the 1980s and 1990s, respectively. The subsequent years saw a paradigm shift in treatment goals from on-demand therapy to prophylactic factor replacement starting at an early age, to prevent hemarthrosis becoming the standard of care for patients with severe hemophilia. In the developed world, the increasing use of home-based prophylactic regimens has significantly improved the quality of life, and life expectancy of patients with severe hemophilia. Seminal developments in the past 5 years, including the commercial availability of extended half-life factor concentrates and the publication of successful results of gene therapy for patients with hemophilia B, promise to further revolutionize hemophilia care over the next few decades. In this review, we summarize the evolution of management for hemophilia, with a focus on extended half-life factor concentrates and gene therapy., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Current developments in haemophilia therapy are directed at two therapeutic targets: reduction of injection frequency and reduction or bypassing of inhibitors. A variety of new molecules addressing these aims are now completing clinical trials and are ready to enter clinical use. First amongst these are modified Factor VIII (FVIII) and Factor IX (FIX) molecules with extended half-lives. FIX modifications have achieved 5-fold prolongation of half-life whilst effects on FVIII have been more modest, at less than two-fold. We now face the problem of integrating these into clinical practice. Other approaches have generated chemically modified FVIII molecules with altered activation profiles. An alternative way of correcting the haemophilia defect is to reduce the activity of natural anticoagulants in an attempt to restore the balance of haemostasis. These methods are also giving promising results but, as with all new approaches, it will be some while before they all find their place in practice., (© 2015 John Wiley & Sons Ltd.)

Up to 14% of individuals with systemic AL amyloidosis develop acquired factor X deficiency, which occurs due to adsorption of factor X onto amyloid fibrils. Although baseline factor X levels are not predictive of bleeding risk in these patients, serious hemorrhagic complications can occur, particularly during invasive procedures. Optimal management strategies to attenuate bleeding risk in these patients are unknown. We describe our experience in the management of acquired factor X deficiency, secondary to systemic AL amyloidosis, in a case series of three patients who received prothrombin complex concentrates (PCCs) for treatment and prevention of bleeding events. We performed a retrospective review extracting information on baseline demographics, laboratory data, pharmacokinetic (PK) studies, and clinically documented bleeding events. Our case series demonstrates that individuals with acquired factor X deficiency secondary to amyloidosis have variable laboratory and clinical responses to PCCs. This is likely due to distinct amyloid loads and fibril sequences, leading to different binding avidities for factor X. Our data emphasize the importance of performing PK testing prior to any invasive procedures to determine the dose and frequency interval to achieve adequate factor X levels for hemostasis, given the variable response between individuals., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hemophilia, when severe, leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions. Most patients must limit their physical activities to avoid bleeding when the factor activity levels are below normal. In 2014, new therapeutic factor VIII and IX products were approved in Canada and the U.S. Over the next couple of years, other new factor products will likely be approved. These new factors have been engineered to have improved pharmacokinetic properties, including extended half-life in circulation, thus providing major therapeutic advances for patients with hemophilia. In the completed clinical trials, over 700 patients have successfully used these longer acting products regularly for more than one year. These promising new therapies should allow patients with hemophilia to use fewer infusions to prevent spontaneous bleeding or to treat bleeding episodes, and to provide appropriate clotting factor levels for different physical activities., (© 2015 International Society on Thrombosis and Haemostasis.)

Background: Edoxaban is an oral, selective direct factor Xa inhibitor approved in Japan for venous thromboembolism prevention after orthopedic surgery. Data are lacking regarding reversal strategies for edoxaban; this study assessed whether four-factor prothrombin complex concentrate (Beriplex/Kcentra; CSL Behring GmbH, Marburg, Germany) can effectively reverse its effects on hemostasis using a previously described rabbit model., Methods: The study comprised assessments of thrombin generation in vitro, pharmacokinetic parameters, and edoxaban reversal in vivo. In a blinded in vivo stage, a standardized kidney incision was performed in animals (n = 11 per group) randomized to receive vehicle + saline, edoxaban (1,200 μg/kg) + saline, or edoxaban (1,200 μg/kg) + four-factor prothrombin complex concentrate (50 IU/kg). Animals were monitored for treatment impact on hemostasis and coagulation parameters. Data are median (range). Statistical tests were adjusted for multiple testing., Results: Edoxaban administration increased blood loss (30 [2 to 44] ml) and time to hemostasis (23 [8.5 to 30.0] min) compared with the control group (3 [1 to 8] ml and 3 [2.0 to 5.0] min, respectively). Biomarkers of coagulation (prothrombin time, activated partial thromboplastin time, whole blood clotting time) and thrombin generation parameters (e.g., peak thrombin, endogenous thrombin potential, lag time) were also affected by edoxaban. Administration of four-factor prothrombin complex concentrate significantly reduced time to hemostasis (to 8 [6.5 to 14.0] min, observed P < 0.0001) and total blood loss (to 9 [4 to 22] ml, observed P = 0.0050) compared with the edoxaban + saline group. Of the biomarkers tested, prothrombin time, whole blood clotting time, and endogenous thrombin potential correlated best with clinical parameters., Conclusion: In a rabbit model of hemostasis, four-factor prothrombin complex concentrate administration significantly decreased edoxaban-associated hemorrhage.

The use of plasma-derived and recombinant coagulation factors for the treatment of haemophilia A and B is well established and permits patients to live a relatively normal life. In order to improve treatment options, several products are in development, which have a prolonged duration of action, thus enabling less frequent prophylactic dosing and aiming to reduce the burden of treatment. Several innovative approaches are being pursued to extend the half-life of factor VIIa, factor VIII and factor IX, utilising technologies such as Fc fusion, recombinant albumin fusion and addition of polyethyleneglycol (PEG) (PEGylation). These methods prolong the time in the circulation by reducing degradation and elimination. This review summarises the technologies and products in development and their stages of development, and also discusses their pros and cons.

Introduction: Hemophilia B is a rare congenital bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). Hemophilia B patients experience mild-to-severe bleeding complications according to the degree of FIX defect. Prophylaxis, with regular infusion of FIX concentrates, is nowadays, the mainstay of hemophilia care. However, because the relatively short half-life of such products necessitates frequent infusions and thus makes patients' adherence difficult, a number of strategies have been implemented to improve the pharmacokinetics of FIX clotting factors., Areas Covered: This review summarizes the main results of Phase I/II and III studies on new FIX molecules engineered to have a longer half-life. Several technologies are being applied to extend FIX half-life, including Fc fusion, recombinant (r) albumin fusion and the addition of PEG polymers., Expert Opinion: By prolonging the FIX half-life up to 5 times, long-acting FIX products are expected to substantially improve the management of hemophilia B patients, allowing less frequent infusions and improving patients' adherence to prophylactic regimens and individualized treatments. Some of them are at an advanced stage of development, such as the rFIX-Fc which has been launched in March 2014. Along with the ongoing Phase III trials, long-term post-marketing surveillance studies are needed to assess their safety and effectiveness and their impact on patients' quality of life.

Some hemophilia A patients who have developed inhibitors are poorly responsive to activated prothrombin complex concentrates (aPCC) after daily dosage, but the mechanism(s) underlying this remain unknown. We examined two representative cases. In case 1, we found that changing to recombinant factor VIIa (rFVIIa) therapy was more effective, and the response to aPCC was restored within ~2 weeks. Tissue factor (TF)-triggered thrombin generation demonstrated a prolonged lag-time and decreased peak thrombin, and this impairment was focused on TF pathway inhibitor (TFPI). Plasma-free TFPI was elevated post-infusion of aPCC, while this was unaffected by rFVIIa. TFPI returned to normal range within 2-3 weeks. Plasmas obtained from patients with poor or good response to aPCC (aPCC-poor or aPCC-good), and good response to rFVIIa (FVIIa-good) demonstrated that free TFPI levels are increased in both aPCC groups, but not in FVIIa-good. TFPI levels pre- and post-infusion in aPCC-poor were significantly higher than those in aPCC-good. Addition of anti-TFPI antibody to the reaction samples demonstrated a greater increase of peak thrombin in aPCC-poor compared to aPCC-good, showing the higher TFPI activity in aPCC-poor. Free TFPI contained in aPCC corresponded to the increasing levels in plasma. In conclusion, TFPI in aPCC attenuated thrombin generation, and the reduced effectiveness of therapy in these circumstances appeared to be related to TFPI activity.

The objectives of this study were to (i) evaluate the predictive performance of pharmacokinetic interspecies scaling of coagulation factors to predict clearance (CL) and (ii) project first-in-human dose based on the predicted human CL. Human CL of nine coagulation factors was predicted using two or three animal species using two methods: (i) CL vs. body weight (simple allometry) and where applicable (ii) the product of CL and brain weight vs. body weight. Based on the predicted human CL, four methods were used to project the first-in-human dose. The predicted pharmacokinetic parameters and the estimated first-in-human dose of coagulation factors were compared with the observed human values obtained from clinical trials. The results of the study indicated that the CL of coagulation factors can be predicted with reasonable accuracy in humans and a good estimate of first-in-human dose can be obtained from the predicted human CL. The suggested methods in this study are not only time and cost-effective but also provide rational alternatives to the somewhat arbitrary dose selection process for coagulation factors often used., (© 2013 John Wiley & Sons Ltd.)

Allometric scaling is a useful tool in early drug development and can be used for the prediction of human pharmacokinetic (PK) parameters from animal PK parameters. The main objective of this work was to predict concentration-time profiles of coagulation factors in humans in a multi-compartment system using animal PK parameters. The prediction of concentration-time profiles in humans in a multi-compartment system was based on the predicted values of clearance and volumes of distribution (V(c), V(ss) and V(β)) from animals. Five coagulation factors from the literature were chosen that were described by two-compartment model in both humans and animals. Clearance and volumes of distribution from animals were allometrically scaled to humans and then were used to predict concentration-time profiles in humans. The predicted concentration-time profile for a given coagulation factor was accurate for most of the time points. Percent prediction error range varied across coagulation factors. The prediction error >50% was observed either at 1 or a maximum of two time points for a given drug. The study indicated that the allometric scaling can be useful in the prediction of concentration-time profiles of coagulation factors in humans from animals and may be helpful in designing a first-in-human study.

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

Prophylaxis is considered the optimal treatment regimen for patients with severe haemophilia, and may be especially important in the prevention of joint disease. Novel coagulation factor concentrates with prolonged half-lives promise to improve patient treatment by enabling prophylaxis with less frequent dosing. With the call to individualize therapy in haemophilia, there is growing awareness of the need to use pharmacokinetic (PK) assessments to tailor prophylaxis. However, for new factor concentrates, it is not yet known which PK values will be most informative for optimizing prophylaxis. This topic was explored at the Eighth Zurich Haemophilia Forum. On the basis of our clinical experience and a discussion of the literature, we report key issues relating to the PK assessment of new coagulation factors and include suggestions on the implementation of PK data to optimize therapy. As both inter- and intra-individual variability in factor half-life have been reported, we suggest that frequent PK assessments should be conducted. However, to diminish the burden of more frequent sampling, sparser sampling strategies and the use of population modelling should be considered. Guidelines on how to assay new factor concentrates, and which PK parameters should be measured, are needed. Concerns were raised regarding the possibility of breakthrough bleeding, and current thinking on how to prevent breakthrough bleeding may no longer be appropriate. Finally, as treatment adherence may be more important to ensure that a therapeutic level of a new coagulation factor concentrate is maintained, behavioural techniques could be implemented to help to improve treatment adherence., (© 2013 John Wiley & Sons Ltd.)

Albumin fusion technology has been used to enhance the pharmacokinetic properties of recombinant coagulation factors. The goal of linking albumin to coagulation factors is to extend the half-life of the coagulation factor, thereby allowing for less frequent dosing for patients with bleeding disorders, such as hemophilia. The novel recombinant fusion proteins linking coagulation factors VIIa and IX with albumin (rVIIa-FP and rIX-FP, respectively) have a longer half-life and similar hemostatic efficacy compared with available recombinant coagulation factor products. Clinical evaluation of these fusion proteins is underway, and preliminary results with rIX-FP in patients with hemophilia B are encouraging. Other advances in coagulation factor therapy include a unique recombinant single-chain factor VIII (FVIII) protein, which has improved intrinsic stability and a higher affinity for von Willebrand factor (VWF), relative to other recombinant FVIIIs, and a recombinant VWF-albumin fusion protein (rVWF-FP), which has a significant longer half-life compared to available VWF products. Evaluation of these novel recombinant proteins continues and will help determine their potential to enhance the management of patients with bleeding disorders., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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.

Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine(®) , a high-purity human FIX concentrate. This open, single-arm, multicentre, non-randomized trial included 25 subjects (age ≥ 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6-month follow-up. The degree of haemostasis control achieved was evaluated during a 12-month follow-up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 ± 0.19 IU dL(-1) per IU kg(-1) at baseline and 1.23 ± 0.34 IU dL(-1) per IU kg(-1) 6 months later. Terminal half-life was 34.5 ± 6.2 h and 33.7 ± 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine(®) were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty-one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine(®) showed a pharmacokinetic profile in agreement with that of other plasma-derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B., (© 2011 Blackwell Publishing Ltd.)

Prothrombin complex concentrate (PCC) infusion is preferred for emergency reversal of coumarin therapy. Rapid infusion can potentially save crucial time; however, the possible impact of high infusion speed on PCC safety and effectiveness has not been delineated. In a prospective multinational clinical trial with 43 patients receiving PCC (Beriplex P/N) for emergency reversal of coumarin therapy, infusion speeds were selected by the investigators. In a two-phase statistical analysis, the influence of baseline patient variables and dose on selected infusion speed was assessed. Then, the effect of infusion speed on reduction in international normalized ratio (INR) and on thrombogenicity marker pharmacokinetics was evaluated. Infusion speed ranged widely from 2.0 to 40.0 mL min(-1) with a median of 7.5 mL min(-1). Selection of infusion speed was not significantly influenced by gender, age, body mass index, presence of acute bleeding, indication for coumarin therapy, baseline INR, or PCC dose. Infusion speed was higher by a median of 2.2 mL min(-1) (95% confidence interval, 1.0-4.3 mL min(-1)) among patients receiving Beriplex P/N volumes > or =80 mL compared with smaller infusion volumes. Infusion speed did not affect INR attained 30 min following PCC infusion. None of the evaluated thrombogenicity marker pharmacokinetic parameters was affected by infusion speed. Infusions in one patient with questionable hemostatic efficacy and another with a possibly PCC-related thromboembolic event were at moderate and slow speeds, respectively. This study provides the first direct evidence that Beriplex P/N can be rapidly infused for emergency coumarin therapy reversal without altering safety or effectiveness.

Optimal replacement treatment in haemophilia B patients requires a good understanding of the pharmacokinetics of factor IX (FIX). The aim of this study was to compare the pharmacokinetic profile of Factor IX Grífols, a highly purified human FIX concentrate with two specific pathogen inactivation/removal steps, to that of available FIX preparations. The study was an open, non-randomized trial including 25 male subjects older than 12 years of age with severe haemophilia B. Pharmacokinetic profile of the FIX preparation regularly used by the subjects was determined as control. Pharmacokinetic profile of Factor IX Grifols was determined twice, one 7-15 days after control assessment and second after a 6 months period had elapsed. Results showed that all products had peak plasma levels of FIX:C within 30 min. Mean recovery was 1.3 +/- 0.3 IU dL(-1) per IU kg(-1) for Factor IX Grifols and 1.0 +/- 0.3 IU dL(-1) per IU kg(-1) for control products (P < 0.001). The mean terminal half-life (t(1/2)) for Factor IX Grifols was 26.7 h and 26.8 h for control product. Pharmacokinetic parameters after 6 months of treatment with Factor IX Grifols did not statistically differ from the parameters obtained with the first infusion. There were no adverse events related to Factor IX Grifols for the duration of the study. In conclusion, Factor IX Grifols has adequated pharmacokinetic properties comparable to the control plasma-derived FIX and these parameters remain stable after 6 months of treatment. Factor IX Grifols can be an effective and safe plasma-derived FIX concentrate for replacement therapy in haemophilia B patients.

Concerns have been raised regarding pharmacokinetic performance, efficacy and safety of B-domain-deleted recombinant FVIII (BDD rFVIII). The objective of this study was to perform a retrospective survey of half-life measurements, efficacy and safety in patients with severe haemophilia A, switching treatment from full-length factor VIII (FL FVIII) to BDD rFVIII and then back to FL FVIII. We hypothesized that half-life of FVIII would be equal regardless of product and that total factor consumption and bleeding frequency would be indistinguishable. We report on inhibitor development and outcome following surgery. Patients with severe haemophilia A, exposed to BDD rFVIII were identified from a database. A retrospective analysis of laboratory data and medical notes was undertaken. No significant difference was detected between the half-life measurements during the switch from FL FVIII (T/2 median 9.15 h, range 6.4-22) to BDD rFVIII (T/2 median 9.7, range 4.7-16.8) and back to FL FVIII (T/2 median 9.0, range 5.0-19.5). There was no significant difference in coagulation factor usage (BDD rFVIII median 4803 IU kg(-1) year(-1), range 659-11 304; FL FVIII median 5349, range 1691-10 146), nor bleeds. Eleven received BDD rFVIII to cover surgical procedures, with no reports of excess bleeding. Thirty-three patients received significant exposure to BDD rFVIII and one developed a low titre inhibitor. BDD rFVIII was found to be equivalent to other FVIII products in terms of pharmacokinetics, clinical efficacy and safety in this study group.

The objective of this study was to evaluate the predictive performance of pharmacokinetic interspecies scaling of coagulation factors and tissue-type plasminogen activators to predict clearance, volume of distribution at steady-state and half-life in humans from animal data. The human pharmacokinetic parameters were predicted using one, two or at least three animal species. The results of the study indicated that the pharmacokinetic parameters of coagulation factors and tissue-type plasminogen activators can be predicted with reasonable accuracy in humans when three or more animal species are available. Two-species scaling can also be performed, but the accuracy of predicted parameters is less than three-species scaling.

The bypassing agents factor eight inhibitor bypassing activity (FEIBA) anti-inhibitor coagulant complex and recombinant activated factor VII (rFVIIa) have been established as safe and effective therapies for treating bleeding episodes in haemophilia patients with inhibitors. However, the efficacy of each bypassing agent can vary, and neither agent is universally effective. The reasons for such variability have yet to be confirmed, but may involve patient-specific factors and the mechanisms of action (MOAs) and pharmacokinetic profiles of these two agents. This issue underscores the necessity of both products in the comprehensive care of patients with haemophilia and inhibitors. The objective of this review is to discuss the evidence of a differential haemostatic response to bypassing agents and the potential roles of MOA and patient-specific factors in contributing to the differences in response.

Objectives: To measure uptake and disposal kinetics and absolute absorption of vitamin K(1) using two stable isotope-labelled forms of vitamin K(1)., Subjects: Ten subjects (nine women and one man) aged between 22 and 31 years, with a mean (+/-standard deviation) body mass index of 22.5+/-2.4 kg/m(2). Subjects took capsules containing 3 microg of methyl-(13)C vitamin K(1), three times a day for six days to reach a steady state for plasma vitamin K(1) isotopic enrichment. On day seven, subjects were given an intravenous dose of Konakion MM to measure disposal kinetics and at the same time, a capsule containing 4 microg of ring-D(4) vitamin K(1) to measure absorption. Plasma vitamin K(1) concentration was measured by high-performance liquid chromatography and isotopic composition by gas chromatography mass spectrometry., Results: The disposal kinetics of the intravenous dose of vitamin K(1) were resolved into two exponentials with half-times of 0.22 (+/-0.14) and 2.66 (+/-1.69) h. Absorption of oral, deuterated vitamin K(1) was 13 (+/-9)%., Conclusions: Two-compartmental kinetic parameters observed in this study are similar to those obtained previously using radioactive tracers, but there may be additional slow-turnover body pools acting as stores of vitamin K(1). The kinetic parameters determined from the intravenous dose allowed determination of the absolute absorption of vitamin K(1) from a bolus oral dose.

Haemophilia patients may require prolonged treatment during peri-operative period or life-threatening bleedings. Intermittent bolus infusions of factor concentrates have been used successfully for many years. However, pharmacokinetics may vary among products and patients, and the wide fluctuations in factor levels during therapy can make management inaccurate and unsafe. Specific protocols for continuous infusion have been developed, which may decrease factor utilization, facilitate laboratory monitoring of factor levels, and may decrease the overall cost of therapy. Continuous infusion of different clotting factor concentrates (factor VIII, factor IX, porcine factor VIII, rFVIIa, and activated prothrombin complex concentrates) has been associated with excellent haemostasis and safety: indeed, by continuous infusion unsafe low troughs or dangerous high concentrations can be avoided. In this review, the pharmacokinetic aspects of the continuous infusion of plasma-derived and recombinant factor IX concentrates are showed. Finally, the advantages and disadvantages of continuous infusion are discussed.

Prothrombin complex concentrates (PCCs) are widely administered for emergency oral anticoagulation reversal and for coagulation defects in liver disease. Pharmacokinetic data may help to optimize treatment. The objective of this study was to characterize the pharmacokinetics of a PCC (Beriplex P/N) containing coagulation factors II (FII), VII (FVII), IX (FIX) and X (FX) and anticoagulant proteins C and S. Fifteen healthy volunteers received a single rapid 50 IU/kg infusion of PCC and underwent frequent blood sampling until 144 hours (h) after infusion. Coagulation factors and anticoagulant protein pharmacokinetic parameters were estimated by non-linear regression. The mean infusion rate of PCC was 7.9 ml/min, equivalent to 196.4 IU/min. By the earliest post-infusion sampling point at 5 minutes (min), plasma FIX concentration increased by a median of 73%. Median increases in FII, FVII and FX at 5 min were 122%, 62% and 158%, respectively. Proteins C and S also increased rapidly. The median terminal half-life of FIX was 16.7 h, FII 59.7 h, FVII 4.2 h and FX 30.7 h. The median in-vivo recovery of FIX was 1.57 %/IU/kg and that of the other three coagulation factors > 2 %/IU/kg. Plasma concentration of thrombogenicity marker D-dimer did not increase, and there was no clinical evidence of thrombosis. Through up to 12 weeks follow-up there were no laboratory findings indicating PCC-related viral exposure. Rapid PCC infusion produced prompt sustained increases in coagulation factors and anticoagulant proteins with no clinical evidence of thrombosis or viral transmission.

A mathematical model has been developed to simulate the generation of thrombin through intrinsic and extrinsic pathways. The time course of clotting factor activation during coagulation was calculated, and the sensitivity of the kinetics due to a decrease or deficiency in the concentrations of coagulation proteins or their activities was studied. The model gives reasonable predictions without the adjustment of any parameter values. The calculated clotting time was approximately 44 s for the intrinsic pathway and approximately 8.6 s for the extrinsic pathway using normal protein concentrations in plasma. Various prolonged clotting times were observed in different factor-deficient disorders using this model.

A subpopulation of patients would benefit from an anticoagulation strategy during extracorporeal circulation (ECC) that does not involve systemic administration of heparin and protamine. Inhibition of coagulation by adsorption of plasma clotting factors using protamine immobilized on a Sepharose matrix (PSM) has been explored. This investigation extends previous in vitro studies and demonstrates the feasibility of heparin-free ECC. In a porcine ex vivo circuit, plasma was separated from blood via plasmapheresis, passed through a column containing PSM beads, and returned to the animal. Hemodialyzers and stents were placed in the circuit before, during, and after ECC and examined for device thrombosis. After 90 minutes, prothrombin time (PT) was prolonged >10 times the baseline, and blood clotting Factors I, II, VIII, and X were decreased significantly (>90%); this state was maintained for 2.5 hours without detectable adverse consequences. After cessation of ECC, PT approached normal levels within 60 minutes. Examination of hemodialyzers and coronary stents placed in the circuit revealed that the removal of clotting factors significantly reduced device thrombosis and that transfusion of homologous blood ( approximately 10% V/V) resulted in immediate restoration of hemostasis. It is possible to remove clotting factors from circulating blood to allow extracorporeal circulation of blood without the use of heparin.

There are increasing reports suggesting that high-dose recombinant human activated factor VII (rFVIIa) is effective in the treatment and prevention of bleeding in patients with quantitative and qualitative platelet disorders. These clinical observations are supported by evidence that FVIIa binds weakly to activated platelet surface and at high concentration improves thrombin generation. In experimental models, this improved thrombin generation enhances platelet adhesion in thrombocytopenic conditions and enhances adhesion and aggregation of platelets lacking glycoprotein IIbIIIa (integrin alpha(IIb)beta(3)), characteristic of the qualitative platelet disorder Glanzmann thrombasthenia (GT). There is a need for clinical trials to confirm the safety and efficacy of rFVIIa in patients with various quantitative and qualitative platelet defects, either by itself or in combination with other hemostatic agents such as platelet transfusion. Pending the availability of such data, rFVIIa may be considered in severe bleeding in thrombocytopenia and GT patients with platelet antibodies and refractory to platelet transfusions and other standard treatments. An international survey suggests that rFVIIa at about 90 microg/kg every 2 hours for 3 or more doses could be used for GT patients with severe bleeding, but confirmation by larger studies is needed. For GT patients undergoing surgery and for treatment and prevention of bleeding in thrombocytopenic patients, the optimal rFVIIa regimen remains to be defined.

Heparin is associated with adverse effects in some patients during extracorporeal circulation. A potential alternate anticoagulation strategy explored in this investigation involved mitigation of coagulation by removing clotting factors from blood by adsorption on a protamine-immobilized Sepharose matrix (PSM). Human or porcine plasmas treated with PSM in vitro were tested for clotting factors I (fibrinogen), II (prothrombin), VIII, and X, and proteins C and S, and for prothrombin time (PT), activated partial thromboplastin time (APTT), and total protein concentration. Bovine blood treated with PSM was also perfused through a hollow-fiber cartridge to assess thrombogenic potential in a shear flow system. PT increased with increasing protamine-Sepharose-to-plasma ratios and with increasing mixing time. When the PT and APTT of treated plasma were prolonged three to six times the baseline, Factors II and X were significantly removed (>90%), Factors I and VIII were partly removed (<35%), and total protein concentration remained >80% of the initial value. When blood depleted of clotting factors was perfused through hollow-fiber cartridges without an anticoagulant, cartridge patency was prolonged compared with cartridges perfused with untreated blood. This investigation demonstrated that inhibition of blood coagulation by removal of key clotting proteins is feasible.

To treat acute episodes of bleeding in patients with hemophilia and low titer inhibitor, "neutralization", which is the neutralization of inhibitors using high dose coagulant factor infusions, is often selected. However, it is difficult to anticipate the dose of continuous infusion (CI) of coagulation products after neutralization. We herein present the CI of coagulant products in 2 patients with hemophilia and low titer inhibitors and discuss the pharmacokinetics of coagulation products. Both patients have had good responses regarding hemostasis using CI after the neutralization. The volume of distribution of coagulation products in case 2 is 3.7 times and clearances of coagulation products are from 2 to 3 times as high as those in patients without inhibitors. It is suspected that the clearances in patients with an inhibitor are higher than those in patients without an inhibitor because a large amount of inhibitor is involved in the extra-vascular space such as tissue fluid and the reticuloendothelial system. The dose for CI of coagulation products after neutralization in patients with inhibitor might be better clarified if the reported cases increase and the pharmacokinetics are more deeply analyzed.