Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors.

The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed.

Immune tolerance induction therapy for patients with hemophilia A and FVIII inhibitors particularly using low-dose regimens.

BACKGROUND: Inhibitory antibodies against infused clotting factor VIII concentrates (FVIII) developed in 20-30% of patients with hemophilia A. Bypass therapy may control the bleeds in patients with FVIII inhibitors, however, immune tolerance induction (ITI) therapy is the only proven modality for eradicating FVIII inhibitors. Since the cost of high-dose (200 IU/kg) ITI is extremely expansive, we conducted this study to identify whether low-dose ITI can be an alternative strategy besides high-dose ITI or bypass therapy. PROCEDURE: Patients with hemophilia A and FVIII inhibitors treated by ITI in Kaohsiung Medical University Hospital from January 2000 to January 2010 were enrolled. Regimens of ITI therapy included high-dose (100 IU/kg) and low-dose (30-50 IU/kg). RESULTS: High-dose ITI therapy for two high responders (HRs) and low-dose ITI therapy for three HRs and all low responders (LRs) were performed. Complete tolerance was achieved in 2 HRs with high-dose regimen, and in one HR and 19 LRs with low-dose regimens. We administered low-dose ITI combined with immune suppressants treatment for one of the patient with extremely high FVIII inhibitor titers and the inhibitor level markedly declined and no spontaneous bleeding episode was noticed during the treatment period. CONCLUSIONS: The outcome of ITI in our study was satisfactory without clinically significant complications. Low-dose ITI regimens can effectively treat patients with high responder inhibitors, including one patient with extremely high inhibitor levels over 700 BU. Low-dose ITI may be an alternative modality for FVIII inhibitors management, especially in countries with limited resources.

Prospective assessment of thrombin generation test for dose monitoring of bypassing therapy in hemophilia patients with inhibitors undergoing elective surgery.

Clinical response to bypassing agents (BPAs) may vary between patients. Surgery is a particular situation, requiring effective hemostasis during the procedure and for several days postoperatively to obtain satisfactory wound healing. However, the optimal dose of BPA in different surgical situations has not been clearly established. We report here a prospective assessment of thrombin generation test (TGT) in monitoring the effectiveness of BPA during 10 elective invasive procedures performed in 6 patients with severe hemophilia and high-titer inhibitors. A standardized 3-step protocol was used in all cases to individually tailor BPA. Thrombin-generating capacity of patients increased after in vitro and ex vivo addition of BPA in a dose-dependent manner. Our results also showed a correlation between in vivo clinical response to BPA and thrombin-generating capacity. These data suggest that TGT may represent a surrogate marker for monitoring bypassing therapies in surgical situations.

Pharmacokinetics, coagulation factor consumption and clinical efficacy in patients being switched from full-length FVIII treatment to B-domain-deleted r-FVIII and back to full-length FVIII.

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.

Successful major and minor surgery using factor VIII inhibitor bypassing activity in patients with haemophilia A and inhibitors.

Surgeries are being increasingly performed in patients with haemophilia A and high-titre inhibitors. Optimal bypassing agent regimens need further delineation. Data pertaining to surgeries from 1989 to 2004 at a single centre were retrospectively analysed. Patients received a standardized factor eight inhibitor bypassing activity (FEIBA) dose for both major and minor elective or emergency surgeries. The standard FEIBA dose was 70 U kg(-1) per infusion. FEIBA was infused at 9 and 1 h before and 8 h after operation. Infusions were routinely repeated every 8 h afterward. Haemostatic efficacy was assessed on the basis of blood loss, occurrence of haematoma and transfusion requirements. Seven adult patients underwent a total of 12 operations: 10 major and two minor. Ten procedures were elective. The median cumulative numbers of infusions and days of therapy were 46 and 17, respectively. Cumulative total FEIBA consumption was a median of 3185 U kg(-1). Observed blood losses, haematoma incidence and transfusion requirements were comparable to those expected for noncoagulopathic patients undergoing similar procedures. The only large haematoma occurred after a hip prosthesis operation and resolved under continuing FEIBA treatment. There were no cases of disseminated intravascular coagulation or other thromboembolic complications. FEIBA provides an effective and safe first-line peri- and postoperative haemostatic therapy for patients with haemophilia A and inhibitors, allowing both major and minor operations to be successfully performed.

Patients', physicians', and pharmacists' preferences towards coagulation factor concentrates to treat haemophilia with inhibitors: results from the COHIBA Study.

Despite modern highly efficacious technologies, there is still a lack of consensus on how to optimally treat haemophilia patients with inhibitors. The aim of the study was to evaluate preferences towards the characteristics of different coagulation factor concentrates for haemophilia inhibitors patients, from the perspective of patients or their caregivers, haematologists and pharmacists. A discrete choice study was conducted. Potential products were described with eight selected characteristics: perceived viral safety, risk of anamnestic response, possibility of undergoing major surgery, frequency of infusions in prophylaxis, number of infusions to stop bleeding, time to stop bleeding, time to pain recovery and cost. Participants received 16 pairs of potential products and chose from each pair the option they considered better. Data were analysed with a random-effects conditional logistic model. Totally 1614 observations were obtained from 37 patients/caregivers, 39 physicians and 25 pharmacists from Italy. Cost was the most important characteristic to every group. For patients/caregivers, the next most important factors were: risk of anamnestic response, possibility of undergoing major surgery and perceived viral safety. For physicians, the next most important characteristics were: risk of anamnestic response, number of infusions to stop bleeding and possibility of undergoing major surgery. For pharmacists, the next most important factors were: time to stop bleeding, time to pain recovery and possibility of undergoing major surgery. Decisions on treatments must take into account patients clinical needs; however, preferences can also play an important role in the choice and success of treatments. The results of this study could, therefore, help decision-makers to optimize the overall benefits of treatments.

Stability, efficacy, and safety of continuously infused sucrose-formulated recombinant factor VIII (rFVIII-FS) during surgery in patients with severe haemophilia.

Bolus injection (BI) of sucrose-formulated recombinant factor VIII (rFVIII-FS) is an approved treatment for haemophilia patients undergoing major surgery. Continuous infusion (CI) during surgery has potential benefits by providing steady administration of replacement factor to the patient, avoiding high peaks and low troughs. We tested the stability of rFVIII-FS under CI conditions and conducted a single-centre, open-label, phase III study to evaluate the efficacy and safety of CI using rFVIII-FS in haemophilia A patients undergoing surgery. Patients received bolus rFVIII-FS to achieve >or=80% FVIII levels 30-60 min presurgery, followed by CI of rFVIII-FS at a rate calculated to maintain haemostatic factor levels until days 8-10 post surgery. The rate of infusion was adjusted according to daily calculations derived from the actual clearance. The stability of rFVIII-FS was found to be appropriate for CI for 7 days under the same conditions as clinical settings. Fourteen patients (mean age 37.8 years) receiving on-demand FVIII treatment without a history of inhibitors underwent 15 surgical procedures including joint replacements, synovectomies, multiple tooth extractions, and cholecystectomy. Bleeding was similar to that observed in non-haemophilia patients undergoing similar operations in the same department. Haemostasis during surgery was considered by the attending surgeons as 'excellent' or 'good' in all cases; study investigators rated all 15 cases as 'excellent' overall. There were no adverse events, including inhibitor formation, related to rFVIII-FS. rFVIII-FS was found to be suitable for use in CI in haemophilia A patients undergoing major surgery.

Immune response to FVIII in hemophilia A: an overview of risk factors.

Development of inhibitors is perhaps the most serious complication of factor VIII (FVIII) replacement therapy, which can practically preclude efficient clinical management of patients with hemophilia A. Much effort therefore has been focused both in improving our understanding of the reasons for the formation of FVIII antibodies and to find alternative methods of treatment. Several patient-related factors have been related to the risk of inhibitor development such as ethnicity, FVIII gene mutation type, family history of inhibitors, HLA haplotype, polymorphisms in the promoter regions of IL 10 gene, single nucleotide polymorphisms of tumor necrosis factor alpha gene, and so on. In addition to the genetic determinants, there are several nongenetic factors which mainly include treatment characteristics like the type and purity of coagulation factor concentrates used for treatment, age at the time of initial treatment, initial doses of concentrate, mode of infusion, surgery, frequency of dosing prior to inhibitor development, and intensity of treatment or regular prophylaxis. Inflammatory processes in early childhood are under discussion as being an environmental factor that may modify the immune response to a foreign antigen. The genetic risks cannot be changed, while environmental factors may increase or decrease the inhibitor risk in an individual patient. In addition, there are other causes of inhibitor development against FVIII like stress, age, malignancy, infection, pregnancy, antibiotics, etc. Development of inhibitors in such cases happens in individuals who are not hemophilic and have normal plasma FVIII levels. Acquired inhibitors to FVIII in nonhemophiliacs (autoantibodies) pose a further challenge to treatment, as this is often associated with significant morbidity and mortality. Prognosis in case of autoantibodies is related to the underlying disease process and is associated with high mortality. Improved understanding of these complex interactions may lead to the development of preventive measures to minimize FVIII inhibitor formation. The modifiable risk factors for inhibitor formation may provide the key to predict and perhaps prevent the formation of inhibitors in hemophilia patients.

Epidemiological survey of haemophiliacs with inhibitors in France: orthopaedic status, quality of life and cost--the 'Statut Orthopédique des Patients Hémophiles' avec Inhibiteur study.

The physical condition of severe haemophilia and the impact of advances in replacement therapy have been much studied, but little work has been done on patients who developed inhibitors. The 'Statut Orthopédique des Patients Hémophiles avec Inhibiteur' study was conducted in France in order to assess the orthopaedic status and quality of life of such patients, and the cost of their medical management. Fifty haemophiliacs aged 12-63 years with a history of high-responder inhibitors were included. Clinical assessment showed that only 12% of the patients had a nil pain score and 2% a nil clinical score, as per Gilbert scale. The mean clinical score was significantly higher in patients over 35 years of age than in younger ones. However, younger patients appeared to have a more impaired orthopaedic status than young haemophiliacs without inhibitors of similar age in previous published cohorts. Surprisingly, older haemophiliacs tended to have the best mental quality of life, contrasting with their highly impaired orthopaedic condition and physical quality of life. The mean cost of clinical resources consumed during the year preceding enrolment was Euro 268 999, 99% of which was related to clotting factor. Marked between-patient differences in cost were noted. Our study suggests that the management of haemophiliacs with inhibitors should be improved in order to prevent haemophilic arthropathy to an extent similar to that of patients without inhibitors. Cost-benefit assessment of any therapeutic strategy should always be combined with quality-of-life evaluation.

Rituximab for the treatment of childhood chronic idiopathic thrombocytopenic purpura and hemophilia with inhibitors.

Rituximab, a monoclonal chimeric antibody to the CD20 antigen, is an effective treatment for non-Hodgkin lymphomas. Moreover, rituximab has also shown efficacy in various autoimmune disorders. In this review, we will focus on the use of rituximab in childhood disorders of hemostasis associated with inhibitor formation. Although the results presented suggest that rituximab can be useful in the treatment of this subset of pediatric patients, most of the data come from isolated case reports or descriptions of small, uncontrolled series. Therefore, large, prospective, and randomized trials are needed to confirm the positive, preliminary results.

New approaches to using FEIBA in the treatment of inhibitor patients.

Managing hemophilia becomes particularly difficult in patients with inhibitory antibodies, especially in those requiring surgery or with refractory bleeding events. Equally challenging are those patients who develop autoantibodies against factor VIII (FVIII) in the absence of a prior history of FVIII deficiency (acquired hemophilia). Physicians seeking both short- and long-term treatment strategies for bleeding events must often rely on FVIII-bypassing agents such as activated prothrombin complex concentrate (e.g., factor eight bypassing activity [FEIBA VH, Baxter BioScience, Westlake Village, CA]) or recombinant factor VIIa (rFVIIa [NovoSeven, NovoNordisk, Bagsvaerd, Denmark]). Surgical procedures in patients with inhibitors present a considerable challenge, from both a risk-benefit and a cost-benefit aspect. Hemostasis is difficult to achieve in these patients and new treatment options are being explored. Similarly challenging are refractory bleeds, the management of which is likely to benefit from a systematic treatment approach.

Discovery and pre-clinical development of antithrombotics from hematophagous invertebrates.

Bloodfeeding (hematophagous) parasites have evolved effective means of inhibiting mammalian thrombosis, thereby facilitating the acquisition and digestion of a bloodmeal. To date, specific inhibitors of coagulation and platelet function have been identified from numerous invertebrate species, representing an impressive array of convergent functional strategies. These parasite antithrombotics, in addition to playing a critical role in the diseases caused or transmitted by bloodfeeding invertebrates, may also serve as potentially useful therapeutic agents for the treatment of a variety of conditions associated with activation of thrombosis. A number of naturally occurring anticoagulants and platelet inhibitors have been evaluated in vivo, with some currently in varying stages of preclinical and clinical development. Because of the unique specificity and potency of parasite antithrombotics, these invertebrate natural products hold great promise for improving the treatment of a variety of human illnesses, including heart disease, stroke, and cancer.

Anticoagulation therapy in children.

Thromboembolic events (TEs) in children are rare but are becoming a recognized cause of morbidity and mortality, particularly in children with serious underlying primary conditions such as congenital heart disease, cancer, or prematurity. Neonates, infants, and adolescents are most at risk for developing TEs among children, and the presence of a central venous line or intra-arterial catheter is the most significant risk factor for TEs in children. Hemostatic differences between children and adults affect both the pathophysiology of the thrombotic process and the response to anticoagulant therapy. In this article, we focus on the impact of the developmental hemostatic system on responses to anticoagulants in children. The most commonly used anticoagulants in children are unfractionated heparin, low-molecular-weight heparins, and warfarin. Minimal experience exists with the use of the new antithrombotic agents in children. As the anticoagulant treatment used for TEs in children is largely adopted from clinical trials performed in adult populations, well-designed prospective trials are required to establish the optimal therapy for children with TEs.